Crystalline solid forms of salts of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n&#39;-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use

ABSTRACT

The invention relates to novel crystalline solid forms of salts of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly renal cell carcinoma (RCC) and medullary thyroid cancer (MTC).

RELATED APPLICATION

This application claims priority to U.S. Application Serial No.62/511,714, filed May 26, 2017. The entire contents of theaforementioned application is incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The invention relates to novel crystalline solid forms of salts of thechemical compoundN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and solvates thereof, includinghydrates, that are useful for the treatment of cancer. Also disclosedare pharmaceutical compositions comprising the crystalline solid formsand processes for making the crystalline solid forms, as well as methodsof using them for the treatment of cancer, particularly renal cellcarcinoma (RCC) and medullary thyroid cancer (MTC).

BACKGROUND OF THE INVENTION

Commonly assigned PCT Patent Publication No. WO 2005/030140,incorporated by reference herein in its entirety, discloses novelinhibitors of multiple receptor tyrosine kinases (RTKs) implicated intumor growth and angiogenesis, pathologic bone remodeling, andmetastatic progression of cancer. In particular, the compoundN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is specifically described in WO2005/030140 as an RTK inhibitor.N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-M-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is also known in the art as cabozantinib.The chemical structure ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (cabozantinib) is represented by Compound1.

Compound 1 was found to have an enzyme Ret IC₅₀ value of about 5.2 nM(dihydrate) and an enzyme c-Met IC₅₀ value of about 1.3 nM (dihydrate).The assay that was used to measure this c-Met activity is described inparagraph [0458] in WO2005/030140.

During initial development experiments, Compound 1 (a free base) wasfound to be a BCS class II compound having low solubility and highpermeability. Because Compound 1 was observed to have low solubility inwater, it was initially considered unsuitable for solid oral dosagedevelopment, and hence the pharmaceutical development focused on findinga salt with suitable hygroscopicity, thermal stability, chemicalstability, physical stability, and solubility.

The malate salt of Compound 1, as described in WO 2010/083414, theentire contents of which is incorporated by reference, was subsequentlyidentified as providing an acceptable combination of crystallinity,solubility, and stability as compared to Compound 1 free base. On Nov.29, 2012, the S-malate salt ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (also known as cabozantinib or COMETRIQ®)was approved by the United States Food and Drug Administration for thetreatment of progressive, metastatic medullary thyroid cancer (MTC). InDecember 2013, the European Committee for Medicinal Products for HumanUse (CHMP), issued a positive opinion on the Marketing AuthorizationApplication (MAA), submitted to the European Medicines Agency, or EMA,for COMETRIQ® for the proposed indication of progressive, unresectable,locally advanced, or metastatic MTC. More recently, in 2015,cabozantinib as the S-malate salt was approved as CABOMETYX® for thetreatment of advance renal cell carcinoma.

Besides therapeutic efficacy, the Applicant continues to endeavor toprovide suitable form(s) of Compound 1 that have favorable propertiesrelated to processing, manufacturing, storage stability, and/orusefulness as a drug. Accordingly, the discovery of new crystallinesolid forms of Compound 1 that possesses some or all of these desiredproperties remains vital to drug development. Thus, disclosed herein arenovel crystalline solid forms of Compound 1 that may be used inpharmaceutical compositions for the treatment of proliferative diseasessuch as cancer.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention, which isdirected to novel crystalline solid forms of salts of Compound 1, aswell as pharmaceutical compositions containing, methods for using, andprocesses for making such crystalline solid forms. The crystalline solidforms include solvated solid forms, including hydrates. Among otheruses, crystalline solid forms of Compound 1 are useful for preparingpharmaceutical compositions expected to have utility in treating cancer.Accordingly, one aspect of the invention pertains to a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a solid form of Compound 1.

As indicated previously, Compound 1 inhibits multiple receptor tyrosinekinases (RTKs) implicated in tumor growth and angiogenesis, pathologicbone remodeling, and metastatic progression of cancer. Accordingly,crystalline solid forms of the Compound 1 are useful for treatingcancer. Thus, another aspect of the invention pertains to a method fortreating cancer comprising administering to a subject a therapeuticallyeffective amount of a solid form of Compound 1 as disclosed herein. Theinvention is also directed to processes for preparing crystalline solidforms of Compound 1.

The solid forms are summarized in Table 1.

TABLE 1 Novel crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′- (4-fluorophenyl)cyclopropane-1,1-dicarboxamide Form Comment 1 Compound 1•citrate,monohydrate, 1:1 2 Compound 1•malonate, 3.6 mol eq water, 1:1 3 Compound1•oxalate, anhydrous, 1:1 4 Compound 1•ethane disulfonate, deliquescent,1:1 5 Compound 1•sulphate, 3.7 mol eq water, 1:1 6 Compound 1•besylate,anhydrous, 1:1 7 Compound 1•esylate, anhydrous, 1:1 8 Novel form relatedto Compound 1 free base 9 Compound 1•mesylate, anhydrous, 1:1 10Compound 1•tosylate, anhydrous, 1:1 11 Compound 1•sulfate, 2.4 mol eqwater, 1:1 12 Compound 1•ethane disulfonate, anhydrous, 2:1 API:acid 13Compound 1•oxalate, anhydrous, 1:1 14 Compound 1•pyruvate, anhydrous,1:1 15 Compound 1•besylate, 1.4 mol. eq. THF, 1:1 16 Compound1•mesylate, dihydrate, 1:1 17 Compound 1•succinate, 0.4 mol eqacetonitrile and 0.86 mol eq water, 1:0.7 API:acid 18 Compound1•esylate, 0.4 mol eq acetonitrile, 1:1 19 Compound 1•isethionate,monohydrate, 1:1 20 Compound 1•glutarate, 0.59 mol eq water, 1:1 21Compound 1•sulfate, monohydrate, 1:1 22 Compound 1•tosylate, 0.8 mol eqwater, 1:1 23 Compound 1•succinate, TGA weight loss equates to ~0.8 moleq of water 24 Compound 1•malonate, anhydrous, 1:1 25 Compound1•mesylate, 0.3 mol eq acetonitrile, 1:1 26 Compound 1•gluconate, 2.6moles water, 1:1 27 Compound 1•isethionate, monohydrate, 1:1

A total of 27 forms were observed during the screen. One of the patterns(Form 8) was free base related. The remaining 26 solids were assessedaccording to their crystallinity, solvation state, stoichiometry, easeof manufacture, deliquescence, stability to desolvation, molecularweight, and acceptability/toleration with respect to oral dosing.Aqueous solubility and optical microscopy were also determined.

In a particular aspect, the invention is directed to crystalline solidsalts ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), wherein the salts areselected from the group consisting of:N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•pyruvate;N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•glutarate; andN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•isethionate monohydrate.

Forms 14, 19, and 20 (pyruvate, glutarate, and isethionate) wereprepared on a 250-1000 mg scale and confirmed as the same forms thatwere observed in the initial screen. The three salts were also fullycharacterized by XRPD, DSC, TG/DTA, DVS, and ¹H NMR microscopy. Aninvestigation into their crystal habit was also performed. Compound 1pyruvate and glutarate were irregular particles with low aspect ratio,whereas Compound 1 isethionate showed a crystal habit of needlemorphology.

The salt forms described herein possess a number of advantageousproperties. Examples of such advantageous properties include a lowermolecular weight giving a higher activity per weight ratio, highersolubility, improved filterability and flow properties due to particlemorphology/aspect ratio, and lower hygroscopicity. Further, many of thesalts described herein are natural human metabolites and are thereforewell-tolerated in vivo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chart showing the XRPD spectra of Forms 1, 2, and 3.

FIG. 2 is a chart showing the XRPD spectra of Forms 4, 5, and 6.

FIG. 3 is a chart showing the XRPD spectra of Forms 7, 8, and 9.

FIG. 4 is a chart showing the XRPD spectra of Forms 10, 11, and 12.

FIG. 5 is a chart showing the XRPD spectra of Forms 13, 14, and 15.

FIG. 6 is a chart showing the XRPD spectra of Forms 16, 17, and 18.

FIG. 7 is a chart showing the XRPD spectra of Forms 19, 20, and 21.

FIG. 8 is a chart showing the XRPD spectra of Forms 22, 23, and 24.

FIG. 9 is a chart showing the XRPD spectra of Forms 25, 26, and 27.

FIG. 10 is the TG/DTA trace of Form 1.

FIG. 11 is the TG/DTA trace of Form 2.

FIG. 12 is the TG/DTA trace of Form 3.

FIG. 13 is the TG/DTA trace of Form 5.

FIG. 14 is the TG/DTA trace of Form 6.

FIG. 15 is the TG/DTA trace of Form 7.

FIG. 16 is the TG/DTA trace of Form 9.

FIG. 17 is the TG/DTA trace of Form 10.

FIG. 18 is the TG/DTA trace of Form 11.

FIG. 19 is the TG/DTA trace of Form 12.

FIG. 20 is the TG/DTA trace of Form 13.

FIG. 21 is the TG/DTA trace of Form 15.

FIG. 22 is the TG/DTA trace of Form 16.

FIG. 23 is the TG/DTA trace of Form 17.

FIG. 24 is the TG/DTA trace of Form 18.

FIG. 25 is the TG/DTA trace of Form 21.

FIG. 26 is the TG/DTA trace of Form 22.

FIG. 27 is the TG/DTA trace of Form 24.

FIG. 28 is the TG/DTA trace of Form 25.

FIG. 29 is the TG/DTA trace of Form 26.

FIG. 30 is the NMR spectrum of Form 1 in DMSO-d₆.

FIG. 31 is the NMR spectrum of Form 2 in DMSO-d₆.

FIG. 32 is the NMR spectrum of Form 3 in DMSO-d₆.

FIG. 33 is the NMR spectrum of Form 5 in DMSO-do.

FIG. 34 is the NMR spectrum of Form 6 in DMSO-d₆.

FIG. 35 is the NMR spectrum of Form 7 in DMSO-d₆.

FIG. 36 is the NMR spectrum of Form 8 in DMSO-d₆.

FIG. 37 is the NMR spectrum of Form 9 in DMSO-d₆.

FIG. 38 is the NMR spectrum of Form 10 in DMSO-d₆.

FIG. 39 is the NMR spectrum of Form 11 in DMSO-d₆.

FIG. 40 is the NMR spectrum of Form 12 in DMSO-d₆.

FIG. 41 is the NMR spectrum of Form 13 in DMSO-d₆.

FIG. 42 is the NMR spectrum of Form 15 in DMSO-d₆.

FIG. 43 is the NMR spectrum of Form 16 in DMSO-d₆.

FIG. 44 is the NMR spectrum of Form 17 in DMSO-d₆.

FIG. 45 is the NMR spectrum of Form 18 in DMSO-d₆.

FIG. 46 is the NMR spectrum of Form 19 in DMSO-d₆.

FIG. 47 is the NMR spectrum of Form 21 in DMSO-d₆.

FIG. 48 is the NMR spectrum of Form 22 in DMSO-d₆.

FIG. 49 is the NMR spectrum of Form 23 in DMSO-d₆.

FIG. 50 is the NMR spectrum of Form 24 in DMSO-d₆.

FIG. 51 is the NMR spectrum of Form 25 in DMSO-d₆.

FIG. 52 is the NMR spectrum of Form 26 in DMSO-d₆.

FIG. 53A is the XRPD spectrum of Form 14, Compound 1 pyruvate.

FIG. 53B is the DSC trace of Form 14, Compound 1 pyruvate.

FIG. 53C is the TG/DTA thermogram of Form 14, Compound 1 pyruvate.

FIG. 53D is the DVS isotherm of Form 14, Compound 1 pyruvate.

FIG. 53E is the XRPD spectrum of Form 14, Compound 1 pyruvate, pre DVS(top) and post DVS (bottom).

FIG. 53F is the FT-IR spectrum of Form 14, Compound 1 pyruvate.

FIG. 53G is the ¹H NMR (DMSO-d⁶) of Form 14, Compound 1 pyruvate.

FIG. 54A is the XRPD spectrum of Form 20, Compound 1 glutarate.

FIG. 54B is the DSC trace of Form 20, Compound 1 glutarate.

FIG. 54C is the TG/DTA thermogram of Form 20, Compound 1 glutarate.

FIG. 54D is the DVS isotherm of Form 20, Compound 1 glutarate.

FIG. 54E is the XRPD spectrum of Form 20, Compound 1 glutarate, pre DVS(top) and post DVS (bottom).

FIG. 54F is the infrared (IR) spectrum of Form 20, Compound 1 glutarate.

FIG. 54G is the ¹H NMR (DMSO-d⁶) of Form 20, Compound 1 glutarate.

FIG. 55A is the XRPD spectrum of Form 27, Compound 1 isethionate,monohydrate.

FIG. 55B is the DSC trace of Form 27, Compound 1 isethionate,monohydrate.

FIG. 55C is the TG/DTA thermogram of Form 27, Compound 1 isethionate,monohydrate.

FIG. 55D is the DVS isotherm of Form 27, Compound 1 isethionate,monohydrate.

FIG. 55E is the XRPD spectrum of Form 27, Compound 1 isethionate,monohydrate, pre DVS (top) and post DVS (bottom).

FIG. 55F is the infrared (IR) spectrum of Form 27, Compound 1isethionate, monohydrate.

FIG. 55G is the ¹H NMR (DMSO-d⁶) of Form 27, Compound 1 isethionate,monohydrate.

DETAILED DESCRIPTION Definitions

Processes described herein can be used to prepare the compositions ofthis invention. The amounts and the features of the components used inthe processes would be as described herein.

When describing the compounds, compositions, methods, and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, i.e., a crystalline Compound 1, and one or moremolecules of a solvent. Such solvates typically have a substantiallyfixed molar ratio of solute and solvent. This term also includesclathrates, including clathrates with water. Representative solventsinclude, for example, water, methanol, ethanol, isopropanol, aceticacid, and the like. When the solvent is water, the solvate formed is ahydrate.

“Therapeutically effective amount” means an amount sufficient to effecttreatment when administered to a subject in need of treatment. “Theamount of a compound of the invention which constitutes a“therapeutically effective amount” will vary depending on the compound,the disease state and its severity, the age of the subject to betreated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art, taking intoconsideration his own knowledge and this disclosure. Thus, a“therapeutically effective amount” of Compound 1 refers to an amountsufficient to treat a subject suffering from any of a variety of cancersassociated with abnormal cell proliferation and angiogenesis. Atherapeutically effective amount according to this disclosure is anamount therapeutically useful for the treatment or prevention of thedisease states and disorders discussed herein. Compound 1 (including thesolid state forms disclosed herein) possess therapeutic activity toinhibit, regulate, and/or modulate the signal transduction of kinasessuch as described in WO2005/030140.

“Treating” or “treatment” as used herein means the treatment of adisease-state in a human, which disease-state is characterized byabnormal cellular proliferation and invasion and includes at least oneof: (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it; (ii) inhibiting the disease-state,i.e., arresting its development; and (iii) relieving the disease-state,i.e., causing regression of the disease-state.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise undesirable. For example, the term“pharmaceutically acceptable carrier” refers to a material that can beincorporated into a composition and administered to a subject withoutcausing undesirable biological effects or interacting in a deleteriousmanner with other components of the composition. Such pharmaceuticallyacceptable materials typically have met the required standards oftoxicological and manufacturing testing and include those materialsidentified as suitable inactive ingredients by the U.S. Food and DrugAdministration.

The term “dosage form” refers to a physically discrete unit suitable fordosing a subject, i.e., each unit containing a predetermined quantity ofa compound of the invention calculated to produce the desiredtherapeutic effect either alone or in combination with one or moreadditional units. For example, such unit dosage forms may be capsules,tablets, pills, and the like.

As used herein, “amorphous” refers to a solid form of a molecule and/orion that is not crystalline. An amorphous solid does not display adefinitive X-ray diffraction pattern with sharp maxima.

As used herein, the term “substantially pure” means the solid form ofCompound 1 referred to contains at least about 90 weight percent basedon the weight of such solid form. The term “at least about 90 weightpercent,” while not intending to limit the applicability of the doctrineof equivalents to the scope of the claims, includes, but is not limitedto, for example, about 90, about 91, about 92, about 93, about 94, about95, about 96, about 97, about 98, about 99, and about 100 weightpercent, based on the weight of the solid form referred to. Theremainder of the solid form of Compound 1 may comprise other solidform(s) of Compound 1 and/or reaction impurities and/or processingimpurities that arise, for example, when the crystalline form isprepared. The presence of reaction impurities and/or processingimpurities may be determined by analytical techniques known in the art,such as, for example, chromatography, nuclear magnetic resonancespectroscopy, mass spectroscopy, and/or infrared spectroscopy.

As used herein “crystalline solids” refers to Compounds or compositionswhere the structural units are arranged in fixed geometric patterns orlattices, so that crystalline solids have rigid long range order. Thestructural units that constitute the crystal structure can be atoms,molecules, or ions. Crystalline solids show definite melting points.

As used herein “the European Pharmacopoeia classification” is a systemwhereby a chemical Compound 1s classified based on hygroscopicity. Theclassification is determined according to Table 2:

TABLE 2 European Pharmacopoeia classification Classification Weightincrease at 80% RH (25° C.) Non hygroscopic <0.2% Slightly hygroscopic≥0.2% and <2% Hygroscopic ≥2% and <15% Very hygroscopic ≥15%Deliquescent sufficient water is absorbed to form a liquidHygroscopicity of a chemical compound can be determined by proceduresknow to those skilled in the art, such as, but not limited to, DynamicVapor Sorption (DVS).

Additionally, unless otherwise stated, structures depicted herein arealso meant to include Compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, Compound 1, whereinone or more hydrogen atoms are replaced deuterium or tritium, or one ormore carbon atoms are replaced by a ¹³C- or ¹⁴C-enriched carbon, arewithin the scope of this invention. Such Compounds are useful, forexample, as analytical tools, probes in biological assays, or Compoundswith improved therapeutic profile.

EMBODIMENTS

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•citrate monohydrate,characterized as Form 1, wherein the crystalline solid comprisesCompound 1 and citrate in a 1:1 molar ratio. In one embodiment, Form 1is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 4.02, 9.61, 13.35, 13.50,15.52, 16.45, 18.49, 20.94, 21.29, 21.50, 21.59, 23.85, 26.83, and 27.12degrees. In another embodiment, Form 1 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 9.61, 13.35, 13.50, 21.50, 23.85, 26.83, and 27.12degrees. In a further embodiment, Form 1 is characterized by peaks at9.61, 13.35, 13.50, 21.50, 23.85, 26.83, and 27.12 degrees on a 2-thetascale in an XRPD pattern. In still a further embodiment, Form 1 ischaracterized by an XRPD pattern according to FIG. 1. In another furtherembodiment, Form 1 is characterized by an XRPD pattern having peakvalues according to Table 3.

TABLE 3 Form 1 2Θ Relative Intensity (%) 4.02 24.46 9.61 42.36 13.3562.09 13.50 38.77 15.52 30.28 16.45 29.05 18.49 27.79 20.94 32.01 21.2929.25 21.50 40.49 21.59 32.63 23.85 100.00 26.83 95.31 27.12 24.41

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•malonate (3.6 molarequivalents of water), characterized as Form 2, wherein the crystallinesolid comprises Compound 1 and malonate in a 1:1 molar ratio. In oneembodiment, Form 2 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 6.36,7.97, 11.99, 12.09, 12.75, 13.64, 17.52, 19.58, 20.57, 21.82, 23.43,24.73, 24.79, 25.01, 26.09, 26.93, 27.36, 27.42, and 27.61 degrees. Inanother embodiment, Form 2 is characterized by one or more peaks on a2-theta scale in an XRPD pattern selected from the group consisting of6.36, 7.97, 12.75, 19.58, 20.57, 23.43, 25.01, 26.93, 27.36, and 27.42degrees. In a further embodiment, Form 2 is characterized by peaks at6.36, 7.97, 12.75, 19.58, 20.57, 23.43, 25.01, 26.93, 27.36, and 27.42degrees on a 2-theta scale in an XRPD pattern. In still a furtherembodiment, Form 2 is characterized by an XRPD pattern according toFIG. 1. In another further embodiment, Form 2 is characterized by anXRPD pattern having peak values according to Table 4.

TABLE 4 Form 2 2Θ Relative Intensity (%) 6.36 56.89 7.97 83.93 11.9924.88 12.09 28.91 12.75 70.21 13.64 30.76 17.52 34.12 19.58 38.24 20.5744.66 21.82 36.96 23.43 44.73 24.73 34.38 24.79 33.11 25.01 43.93 26.0936.33 26.93 100.00 27.36 81.02 27.42 92.63 27.61 35.74

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•oxalate (anhydrous),characterized as Form 3, wherein the crystalline solid comprisesCompound 1 and oxalate in a 1:1 molar ratio. In one embodiment, Form 3is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 7.40, 9.44, 9.78, 10.36,12.67, 12.97, 13.60, 14.42, 15.87, 18.65, 19.06, 21.21, 22.05, 22.76,23.07, 24.89, and 25.69 degrees. In another embodiment, Form 3 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 9.78, 10.36, 12.97, 13.60, 23.07,and 25.69 degrees. In a further embodiment, Form 3 is characterized bypeaks at 9.78, 10.36, 12.97, 13.60, 23.07, and 25.69 degrees on a2-theta scale in an XRPD pattern. In still a further embodiment, Form 3is characterized by an XRPD pattern according to FIG. 1. In anotherfurther embodiment, Form 3 is characterized by an XRPD pattern havingpeak values according to Table 5.

TABLE 5 Form 3 2Θ Relative Intensity (%) 7.40 35.52 9.44 29.34 9.7885.32 10.36 53.05 12.67 27.37 12.97 43.74 13.60 100.00 14.42 29.48 15.8728.88 18.65 29.21 19.06 28.47 21.21 27.88 22.05 31.42 22.76 34.96 23.0748.76 24.89 29.47 25.69 73.85

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•ethane disulfonate(deliquescent), characterized as Form 4, wherein the crystalline solidcomprises Compound 1 and ethane disulfonate in a 1:1 molar ratio. In oneembodiment, Form 4 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 6.83,8.37, 11.67, 13.10, 13.65, 22.09, 22.48, 22.70, 24.66, and 27.19degrees. In another embodiment, Form 4 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 8.37, 11.67, 13.10, 22.48, 22.70, 24.66, and 27.19degrees. In a further embodiment, Form 4 is characterized by peaks at8.37, 11.67, 13.10, 22.48, 22.70, 24.66, and 27.19 degrees on a 2-thetascale in an XRPD pattern. In still a further embodiment, Form 4 ischaracterized by an XRPD pattern according to FIG. 2. In another furtherembodiment, Form 4 is characterized by an XRPD pattern having peakvalues according to Table 6.

TABLE 6 Form 4 2Θ Relative Intensity (%) 6.83 24.03 8.37 36.97 11.6747.17 13.10 65.30 13.65 27.64 22.09 30.92 22.48 51.17 22.70 38.88 24.66100.00 27.19 56.32

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•sulfate (3.7 molarequivalents of water), characterized as Form 5, wherein the crystallinesolid comprises Compound 1 and sulfate in a 1:1 molar ratio. In oneembodiment, Form 5 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 9.56,10.08, 13.29, 13.86, 14.17, 22.27, 22.60, 22.93, 25.16, and 27.70degrees. In another embodiment, Form 5 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 9.56, 10.08, 13.29, 13.86, 22.60, and 25.16 degrees. In afurther embodiment, Form 5 is characterized by peaks at 9.56, 10.08,13.29, 13.86, 22.60, and 25.16 degrees on a 2-theta scale in an XRPDpattern. In still a further embodiment, Form 5 is characterized by anXRPD pattern according to FIG. 2. In another further embodiment, Form 5is characterized by an XRPD pattern having peak values according toTable 7.

TABLE 7 Form 5 2Θ Relative Intensity (%) 9.56 31.55 10.08 54.68 13.29100.00 13.86 29.19 14.17 25.67 22.27 29.42 22.60 32.23 22.93 22.45 25.1642.68 27.70 22.46

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•besylate (anhydrous),characterized as Form 6, wherein the crystalline solid comprisesCompound 1 and besylate in a 1:1 molar ratio. In one embodiment, Form 6is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 9.77, 10.52, 13.26, 14.34,15.90, 15.98, 17.93, 18.69, 19.54, 22.83, 26.78, and 26.85 degrees. Inanother embodiment, Form 6 is characterized by one or more peaks on a2-theta scale in an XRPD pattern selected from the group consisting of9.77, 10.52, 13.26, 14.34, 15.90, 18.69, 19.54, 22.83, 26.78, and 26.85degrees. In a further embodiment, Form 6 is characterized by peaks at9.77, 10.52, 13.26, 14.34, 15.90, 18.69, 19.54, 22.83, 26.78, and 26.85degrees on a 2-theta scale in an XRPD pattern. In still a furtherembodiment, Form 6 is characterized by an XRPD pattern according to FIG.2. In another further embodiment, Form 6 is characterized by an XRPDpattern having peak values according to Table 8.

TABLE 8 Form 6 2Θ Relative Intensity (%) 9.77 49.49 10.52 50.51 13.2643.13 14.34 60.99 15.90 63.28 15.98 39.22 17.93 28.79 18.69 95.51 19.5498.11 22.83 44.56 26.78 100.00 26.85 49.18

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•esylate (anhydrous),characterized as Form 7, wherein the crystalline solid comprisesCompound 1 and esylate in a 1:1 molar ratio. In one embodiment, Form 7is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 5.18, 11.63, 14.09, 14.79,16.89, 19.92, 21.05, and 26.46 degrees. In another embodiment, Form 7 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 14.79 and 19.92 degrees. In afurther embodiment, Form 7 is characterized by peaks at 14.79 and 19.92degrees on a 2-theta scale in an XRPD pattern. In still a furtherembodiment, Form 7 is characterized by an XRPD pattern according to FIG.3. In another further embodiment, Form 7 is characterized by an XRPDpattern having peak values according to Table 9.

TABLE 9 Form 7 2Θ Relative Intensity (%) 5.18 13.98 11.63 21.79 14.0913.92 14.79 34.44 16.89 26.58 19.92 100.00 21.05 14.72 26.46 21.78

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), characterized as Form 8(free base). In one embodiment, Form 8 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 6.76, 12.35, 12.85, 18.88, 21.01, 22.83, 23.59, 25.10,26.30, 27.96, and 28.02 degrees. In another embodiment, Form 8 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 12.35, 12.85, 18.88, 21.01, 22.83,23.59, 25.10, and 26.30 degrees. In a further embodiment, Form 8 ischaracterized by peaks at 12.35, 12.85, 18.88, 21.01, 22.83, 23.59,25.10, and 26.30 degrees on a 2-theta scale in an XRPD pattern. In stilla further embodiment, Form 8 is characterized by an XRPD patternaccording to FIG. 3. In another further embodiment, Form 8 ischaracterized by an XRPD pattern having peak values according to Table10.

TABLE 10 Form 8 2Θ Relative Intensity (%) 6.76 36.60 12.35 83.87 12.8593.30 18.88 41.62 21.01 57.43 22.83 59.91 23.59 100.00 25.10 86.37 26.3046.74 27.96 30.77 28.02 34.16

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•mesylate (anhydrous),characterized as Form 9, wherein the crystalline solid comprisesCompound 1 and mesylate in a 1:1 molar ratio. In one embodiment, Form 9is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 5.75, 11.33, 15.57, 16.19,16.34, 16.76, 17.36, 17.90, 20.87, 22.69, and 23.08 degrees. In anotherembodiment, Form 9 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 5.75,15.57, 16.19, 17.90, 20.87, 22.69, and 23.08 degrees. In a furtherembodiment, Form 9 is characterized by peaks at 5.75, 15.57, 16.19,17.90, 20.87, 22.69, and 23.08 degrees on a 2-theta scale in an XRPDpattern. In still a further embodiment, Form 9 is characterized by anXRPD pattern according to FIG. 3. In another further embodiment, Form 9is characterized by an XRPD pattern having peak values according toTable 11.

TABLE 11 Form 9 2Θ Relative Intensity (%) 5.75 77.52 11.33 23.45 15.5748.39 16.19 52.53 16.34 34.44 16.76 37.72 17.36 39.23 17.90 89.49 20.87100.00 22.69 45.69 23.08 46.44

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-M-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•tosylate (anhydrous),characterized as Form 10, wherein the crystalline solid comprisesCompound 1 and tosylate in a 1:1 molar ratio. In one embodiment, Form 10is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 4.77, 9.58, 14.17, 14.26,15.55, 15.61, 18.20, 18.29, 19.30, 20.12, 26.13, 26.20, 27.11, and 28.99degrees. In another embodiment, Form 10 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 15.55, 18.29, 19.30, 20.12, 26.13, and 26.20 degrees. In afurther embodiment, Form 10 is characterized by peaks at 15.55, 18.29,19.30, 20.12, 26.13, and 26.20 degrees on a 2-theta scale in an XRPDpattern. In still a further embodiment, Form 10 is characterized by anXRPD pattern according to FIG. 4. In another further embodiment, Form 10is characterized by an XRPD pattern having peak values according toTable 12.

TABLE 12 Form 10 2Θ Relative Intensity (%) 4.77 11.91 9.58 30.05 14.1726.31 14.26 20.29 15.55 34.55 15.61 29.75 18.20 33.26 18.29 55.08 19.3068.74 20.12 37.56 26.13 100.00 26.20 63.10 27.11 20.63 28.99 15.17

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•sulfate (2.4 molarequivalents of water), characterized as Form 11, wherein the crystallinesolid comprises Compound 1 and sulfate in a 1:1 molar ratio. In oneembodiment, Form 11 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 6.75,9.64, 11.06, 12.70, 13.70, 13.92, 14.76, 21.13, 23.58, 24.46, 24.52,26.66, 27.62, and 29.81 degrees. In another embodiment, Form 11 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 12.70, 13.92, 23.58, 24.46, 24.52,and 26.66 degrees. In a further embodiment, Form 11 is characterized bypeaks at 12.70, 13.92, 23.58, 24.46, 24.52, and 26.66 degrees on a2-theta scale in an XRPD pattern. In still a further embodiment, Form 11is characterized by an XRPD pattern according to FIG. 4. In anotherfurther embodiment, Form 11 is characterized by an XRPD pattern havingpeak values according to Table 13.

TABLE 13 Form 11 2Θ Relative Intensity (%) 6.75 24.55 9.64 22.13 11.0622.35 12.70 86.90 13.70 30.12 13.92 100.00 14.76 33.17 21.13 31.01 23.5855.23 24.46 43.65 24.52 42.57 26.66 73.75 27.62 36.17 29.81 27.23

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•ethane disulfonate(anhydrous), characterized as Form 12, wherein the crystalline solidcomprises Compound 1 and ethane disulfonate in a 2:1 molar ratio(Compound 1 to disulfonate). In one embodiment, Form 12 is characterizedby one or more peaks on a 2-theta scale in an XRPD pattern selected fromthe group consisting of 13.20, 13.75, 14.56, 16.45, 16.74, 18.07, 18.23,20.18, 22.28, 23.46, 24.98, 25.69, 27.62, and 31.26 degrees. In anotherembodiment, Form 12 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 13.20,13.75, 14.56, 20.18, 22.28, 24.98, and 25.69 degrees. In a furtherembodiment, Form 12 is characterized by peaks at 13.20, 13.75, 14.56,20.18, 22.28, 24.98, and 25.69 degrees on a 2-theta scale in an XRPDpattern. In another further embodiment, Form 12 is characterized bypeaks at 13.20, 14.56, 20.18, 22.28, 24.98, and 25.69 degrees on a2-theta scale in an XRPD pattern. In still a further embodiment, Form 12is characterized by an XRPD pattern according to FIG. 4. In anotherfurther embodiment, Form 12 is characterized by an XRPD pattern havingpeak values according to Table 14.

TABLE 14 Form 12 2θ Relative Intensity (%) 13.20 56.12 13.75 30.38 14.5659.77 16.45 31.95 16.74 32.59 18.07 25.49 18.23 36.19 20.18 96.92 22.28100.00 23.46 29.93 24.98 52.41 25.69 43.16 27.62 27.04 31.26 23.92

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•oxalate (anhydrous),characterized as Form 13, wherein the crystalline solid comprisesCompound 1 and oxalate in a 1:1 molar ratio. In one embodiment, Form 13is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 12.67, 12.86, 13.63,20.83, 21.28, 22.65, 23.59, 25.89, 26.55, and 26.60 degrees. In anotherembodiment, Form 13 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 12.67,13.63, 20.83, 22.65, 23.59, and 26.55 degrees. In a further embodiment,Form 13 is characterized by peaks at 12.67, 13.63, 20.83, 22.65, 23.59,and 26.55 degrees on a 2-theta scale in an XRPD pattern. In anotherfurther embodiment, Form 13 is characterized by peaks at 12.67, 13.63,22.65, 23.59, and 26.55 degrees on a 2-theta scale in an XRPD pattern.In still a further embodiment, Form 13 is characterized by an XRPDpattern according to FIG. 5. In another further embodiment, Form 13 ischaracterized by an XRPD pattern having peak values according to Table15.

TABLE 15 Form 13 2θ Relative Intensity (%) 12.67 49.07 12.86 28.41 13.6365.97 20.83 37.19 21.28 27.03 22.65 100.00 23.59 45.84 25.89 29.45 26.5539.75 26.60 35.81

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•pyruvate (anhydrous),characterized as Form 14, wherein the crystalline solid comprisesCompound 1 and pyruvate in a 1:1 molar ratio. In one embodiment, Form 14is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 7.84, 8.81, 11.58, 15.67,16.30, 16.55, 17.67, 17.92, 18.00, 18.20, 18.62, 19.66, 20.54, 20.75,23.84, 26.35, and 26.42 degrees. In another embodiment, Form 14 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 8.81, 17.67, 23.84, and 26.42degrees. In a further embodiment, Form 14 is characterized by peaks at8.81, 17.67, 23.84, and 26.42 degrees on a 2-theta scale in an XRPDpattern. In another further embodiment, Form 14 is characterized bypeaks at 8.81, 11.58, 17.67, 18.00, 23.84, and 26.35 degrees on a2-theta scale in an XRPD pattern. In still a further embodiment, Form 14is characterized by an XRPD pattern according to FIG. 5. In anotherfurther embodiment, Form 14 is characterized by an XRPD pattern havingpeak values according to Table 16.

TABLE 16 Form 14 2θ Relative Intensity (%) 7.84 19.94 8.81 29.73 11.5828.31 15.67 22.49 16.30 22.56 16.55 19.61 17.67 33.68 17.92 21.55 18.0024.02 18.20 18.83 18.62 19.80 19.66 16.87 20.54 16.54 20.75 21.33 23.84100.00 26.35 34.88 26.42 22.64

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•besylate (1.4 molarequivalents of tetrahydrofuran), characterized as Form 15, wherein thecrystalline solid comprises Compound 1 and besylate in a 1:1 molarratio. In one embodiment, Form 15 is characterized by one or more peakson a 2-theta scale in an XRPD pattern selected from the group consistingof 5.75, 10.42, 13.04, 15.59, 16.47, 17.95, 18.17, 18.85, 19.41, 20.90,22.50, 23.24, and 24.36 degrees. In another embodiment, Form 15 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 5.75, 10.42, 15.59, 16.47, and24.36 degrees. In a further embodiment, Form 15 is characterized bypeaks at 5.75, 10.42, 15.59, 16.47, and 24.36 degrees on a 2-theta scalein an XRPD pattern. In another further embodiment, Form 15 ischaracterized by peaks at 5.75, 10.42, 15.59, 16.47, 17.95, 18.17, and24.36 degrees on a 2-theta scale in an XRPD pattern. In still a furtherembodiment, Form 15 is characterized by an XRPD pattern according toFIG. 5. In another further embodiment, Form 15 is characterized by anXRPD pattern having peak values according to Table 17.

TABLE 17 Form 15 2θ Relative Intensity (%) 5.75 100.00 10.42 52.58 13.0418.12 15.59 34.24 16.47 39.17 17.95 30.64 18.17 34.46 18.85 25.65 19.4120.77 20.90 24.88 22.50 30.47 23.24 29.38 24.36 40.92

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•mesylate dihydrate,characterized as Form 16, wherein the crystalline solid comprisesCompound 1 and mesylate in a 1:1 molar ratio. In one embodiment, Form 16is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 6.71, 9.70, 10.76, 13.35,13.47, 15.67, 16.20, 18.65, 19.09, 19.33, 21.77, 21.87, 23.00, 23.98,25.25, 26.86, and 27.19 degrees. In another embodiment, Form 16 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 9.70, 13.47, 21.77, 21.87, 23.98,and 26.86 degrees. In a further embodiment, Form 16 is characterized bypeaks at 9.70, 13.47, 21.77, 21.87, 23.98, and 26.86 degrees on a2-theta scale in an XRPD pattern. In another further embodiment, Form 16is characterized by peaks at 9.70, 13.35, 13.47, 19.33, 21.77, 21.87,23.98, and 26.86 degrees on a 2-theta scale in an XRPD pattern. In stilla further embodiment, Form 16 is characterized by an XRPD patternaccording to FIG. 6. In another further embodiment, Form 16 ischaracterized by an XRPD pattern having peak values according to Table18.

TABLE 18 Form 16 2θ Relative Intensity (%) 6.71 18.17 9.70 59.63 10.7625.96 13.35 44.84 13.47 100.00 15.67 35.43 16.20 25.26 18.65 25.03 19.0925.70 19.33 37.30 21.77 48.80 21.87 49.48 23.00 25.44 23.98 91.31 25.2529.44 26.86 50.21 27.19 35.69

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•succinate (0.4 molarequivalents of acetonitrile and 0.86 molar equivalents of water),characterized as Form 17, wherein the crystalline solid comprisesCompound 1 and succinate in a 1:0.7 molar ratio (Compound 1 tosuccinate). In one embodiment, Form 17 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 5.96, 6.74, 11.88, 12.15, 13.69, 13.74, 16.47, 20.43,20.70, 22.85, 24.69, 24.76, and 26.59 degrees. In another embodiment,Form 17 is characterized by one or more peaks on a 2-theta scale in anXRPD pattern selected from the group consisting of 5.96, 6.74, 11.88,13.74, 20.70, and 24.76 degrees. In a further embodiment, Form 17 ischaracterized by peaks at 5.96, 6.74, 11.88, 13.74, 20.70, and 24.76degrees on a 2-theta scale in an XRPD pattern. In another furtherembodiment, Form 17 is characterized by peaks at 6.74, 11.88, 20.70,24.69, 24.76, and 26.59 degrees on a 2-theta scale in an XRPD pattern.In still a further embodiment, Form 17 is characterized by an XRPDpattern according to FIG. 6. In another further embodiment, Form 17 ischaracterized by an XRPD pattern having peak values according to Table19.

TABLE 19 Form 17 2θ Relative Intensity (%) 5.96 34.77 6.74 82.57 11.88100.00 12.15 36.46 13.69 33.30 13.74 36.80 16.47 35.44 20.43 37.25 20.7057.89 22.85 30.96 24.69 61.62 24.76 59.65 26.59 43.91

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-M-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•esylate (0.4 molarequivalents of acetonitrile), characterized as Form 18, wherein thecrystalline solid comprises Compound 1 and esylate in a 1:1 molar ratio.In one embodiment, Form 18 is characterized by one or more peaks on a2-theta scale in an XRPD pattern selected from the group consisting of9.45, 9.86, 15.31, 16.85, 20.83, 21.72, 22.82, and 24.60 degrees. Inanother embodiment, Form 18 is characterized by one or more peaks on a2-theta scale in an XRPD pattern selected from the group consisting of9.45, 9.86, 20.83, and 21.72 degrees. In a further embodiment, Form 18is characterized by peaks at 9.45, 9.86, 20.83, and 21.72 degrees on a2-theta scale in an XRPD pattern. In another further embodiment, Form 18is characterized by peaks at 9.45, 9.86, 20.83, 21.72, and 24.60 degreeson a 2-theta scale in an XRPD pattern. In still a further embodiment,Form 18 is characterized by an XRPD pattern according to FIG. 6. Inanother further embodiment, Form 18 is characterized by an XRPD patternhaving peak values according to Table 20.

TABLE 20 Form 18 2θ Relative Intensity (%) 9.45 50.39 9.86 54.92 15.3125.33 16.85 25.19 20.83 100.00 21.72 67.97 22.82 25.97 24.60 42.96

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•isethionate monohydrate,characterized as Form 19, wherein the crystalline solid comprisesCompound 1 and isethionate in a 1:1 molar ratio. In one embodiment, Form19 is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 8.54, 11.10, 12.22, 12.67,14.12, 17.19, 18.73, 22.19, and 24.33 degrees. In another embodiment,Form 19 is characterized by one or more peaks on a 2-theta scale in anXRPD pattern selected from the group consisting of 8.54, 12.67, 22.19,and 24.33 degrees. In a further embodiment, Form 19 is characterized bypeaks at 8.54, 12.67, 22.19, and 24.33 degrees on a 2-theta scale in anXRPD pattern. In a further embodiment, Form 19 is characterized by peaksat 8.54, 11.10, 12.67, 14.12, 22.19, and 24.33 degrees on a 2-thetascale in an XRPD pattern. In still a further embodiment, Form 19 ischaracterized by an XRPD pattern according to FIG. 7. In another furtherembodiment, Form 19 is characterized by an XRPD pattern having peakvalues according to Table 21.

TABLE 21 Form 19 2θ Relative Intensity (%) 8.54 100.00 11.10 40.77 12.2238.21 12.67 72.83 14.12 41.22 17.19 37.21 18.73 38.42 22.19 49.83 24.3344.13

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•glutarate (0.59 molarequivalents of water), characterized as Form 20, wherein the crystallinesolid comprises Compound 1 and glutarate in a 1:1 molar ratio. In oneembodiment, Form 20 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 8.06,11.77, 19.97, 20.21, 22.27, 23.11, 23.17, 25.81, 25.87, 26.00, and 26.06degrees. In another embodiment, Form 20 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 8.06, 11.77, 20.21, 22.27, and 26.06 degrees. In a furtherembodiment, Form 20 is characterized by peaks at 8.06, 11.77, 20.21,22.27, and 26.06 degrees on a 2-theta scale in an XRPD pattern. In afurther embodiment, Form 20 is characterized by peaks at 8.06, 11.77,20.21, 22.27, 23.11, 25.81, 25.87, and 26.00 degrees on a 2-theta scalein an XRPD pattern. In still a further embodiment, Form 20 ischaracterized by an XRPD pattern according to FIG. 7. In another furtherembodiment, Form 20 is characterized by an XRPD pattern having peakvalues according to Table 22.

TABLE 22 Form 20 2θ Relative Intensity (%) 8.06 47.38 11.77 46.03 19.9741.28 20.21 55.57 22.27 100.00 23.11 71.55 23.17 39.02 25.81 78.71 25.8751.94 26.00 49.11 26.06 36.46

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•sulfate monohydrate,characterized as Form 21, wherein the crystalline solid comprisesCompound 1 and sulfate in a 1:1 molar ratio. In one embodiment, Form 21is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 6.61, 13.26, 13.60, 14.67,16.40, 17.66, 19.96, 20.37, 20.76, 21.09, 21.25, and 23.30 degrees. Inanother embodiment, Form 21 is characterized by one or more peaks on a2-theta scale in an XRPD pattern selected from the group consisting of6.61, 13.60, 20.37, 20.76, 21.09, and 23.30 degrees. In a furtherembodiment, Form 21 is characterized by peaks at 6.61, 13.60, 20.37,20.76, 21.09, and 23.30 degrees on a 2-theta scale in an XRPD pattern.In another further embodiment, Form 21 is characterized by peaks at13.60, 20.37, 20.76, 21.09, and 23.30 degrees on a 2-theta scale in anXRPD pattern. In still a further embodiment, Form 21 is characterized byan XRPD pattern according to FIG. 7. In another further embodiment, Form21 is characterized by an XRPD pattern having peak values according toTable 23.

TABLE 23 Form 21 2θ Relative Intensity (%) 6.61 48.77 13.26 40.99 13.6091.27 14.67 42.40 16.40 37.43 17.66 42.58 19.96 34.17 20.37 58.18 20.7666.31 21.09 52.18 21.25 40.45 23.30 100.00

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•tosylate (0.8 molarequivalents of water), characterized as Form 22, wherein the crystallinesolid comprises Compound 1 and tosylate in a 1:1 molar ratio. In oneembodiment, Form 22 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 13.75,14.20, 14.77, 18.05, 19.28, 19.88, 20.51, 22.63, 25.41, 25.48, and 27.29degrees. In another embodiment, Form 22 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 13.75, 14.77, 18.05, 19.88, 22.63, and 25.41 degrees. In afurther embodiment, Form 22 is characterized by peaks at 13.75, 14.77,18.05, 19.88, 22.63, and 25.41 degrees on a 2-theta scale in an XRPDpattern. In still a further embodiment, Form 22 is characterized by anXRPD pattern according to FIG. 8. In another further embodiment, Form 22is characterized by an XRPD pattern having peak values according toTable 24.

TABLE 24 Form 22 2θ Relative Intensity (%) 13.75 64.13 14.20 37.16 14.7766.83 18.05 100.00 19.28 35.53 19.88 55.33 20.51 42.49 22.63 64.15 25.4189.50 25.48 52.94 27.29 38.14

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•succinate (0.8 molarequivalents of water), characterized as Form 23, wherein the crystallinesolid comprises Compound 1 and succinate in a 1:0.6 molar ratio. In oneembodiment, Form 23 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 6.35,11.82, 12.20, 12.47, 13.76, 17.86, 18.04, 20.96, 21.96, 22.96, 23.79,24.10, 24.96, and 25.59 degrees. In another embodiment, Form 23 ischaracterized by one or more peaks on a 2-theta scale in an XRPD patternselected from the group consisting of 11.82, 12.47, 22.96, and 24.96degrees. In a further embodiment, Form 23 is characterized by peaks at11.82, 12.47, 22.96, and 24.96 degrees on a 2-theta scale in an XRPDpattern. In another further embodiment, Form 23 is characterized bypeaks at 11.82, 12.47, 17.86, 22.96, 23.79, and 24.96 degrees on a2-theta scale in an XRPD pattern. In still a further embodiment, Form 23is characterized by an XRPD pattern according to FIG. 8. In anotherfurther embodiment, Form 23 is characterized by an XRPD pattern havingpeak values according to Table 25.

TABLE 25 Form 23 2θ Relative Intensity (%) 6.35 37.04 11.82 85.55 12.2045.18 12.47 100.00 13.76 35.31 17.86 64.71 18.04 40.96 20.96 36.92 21.9649.64 22.96 76.81 23.79 61.31 24.10 50.29 24.96 80.63 25.59 48.68

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•malonate (anhydrous),characterized as Form 24, wherein the crystalline solid comprisesCompound 1 and malonate in a 1:1 molar ratio. In one embodiment, Form 24is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 6.77, 12.36, 12.86, 21.02,22.85, 23.61, 25.12, 26.31, 28.01, and 30.36 degrees. In anotherembodiment, Form 24 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 12.36,12.86, 21.02, 22.85, 23.61, and 25.12 degrees. In a further embodiment,Form 24 is characterized by peaks at 12.36, 12.86, 21.02, 22.85, 23.61,and 25.12 degrees on a 2-theta scale in an XRPD pattern. In still afurther embodiment, Form 24 is characterized by an XRPD patternaccording to FIG. 8. In another further embodiment, Form 24 ischaracterized by an XRPD pattern having peak values according to Table26.

TABLE 26 Form 24 2θ Relative Intensity (%) 6.77 35.81 12.36 80.89 12.8683.28 21.02 54.92 22.85 62.92 23.61 80.96 25.12 100.00 26.31 38.90 28.0137.61 30.36 20.24

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•mesylate (0.3 molarequivalents of acetonitrile), characterized as Form 25, wherein thecrystalline solid comprises Compound 1 and mesylate in a 1:1 molarratio. In one embodiment, Form 25 is characterized by one or more peakson a 2-theta scale in an XRPD pattern selected from the group consistingof 9.42, 9.75, 10.72, 11.98, 15.52, 17.71, 19.51, 19.66, 21.65, 21.96,22.54, 23.35, 24.55, and 25.92 degrees. In another embodiment, Form 25is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 9.42, 9.75, 19.66, 21.65,22.54, 23.35, and 24.55 degrees. In a further embodiment, Form 25 ischaracterized by peaks at 9.42, 9.75, 19.66, 21.65, 22.54, 23.35, and24.55 degrees on a 2-theta scale in an XRPD pattern. In still a furtherembodiment, Form 25 is characterized by an XRPD pattern according toFIG. 9. In another further embodiment, Form 25 is characterized by anXRPD pattern having peak values according to Table 27.

TABLE 27 Form 25 2θ Relative Intensity (%) 9.42 36.69 9.75 100.00 10.7217.26 11.98 29.71 15.52 26.67 17.71 19.68 19.51 20.00 19.66 38.10 21.6584.01 21.96 17.63 22.54 73.54 23.35 56.68 24.55 37.86 25.92 33.51

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-M-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•gluconate (2.6 molarequivalents of water), characterized as Form 26, wherein the crystallinesolid comprises Compound 1 and gluconate in a 1:1 molar ratio. In oneembodiment, Form 26 is characterized by one or more peaks on a 2-thetascale in an XRPD pattern selected from the group consisting of 10.50,10.59, 13.58, 13.98, 14.05, 18.71, 21.01, 22.59, 23.24, 24.35, 25.38,25.46, 26.73, 26.88, 27.40, and 27.96 degrees. In another embodiment,Form 26 is characterized by one or more peaks on a 2-theta scale in anXRPD pattern selected from the group consisting of 13.58, 13.98, 22.59,and 25.46 degrees. In a further embodiment, Form 26 is characterized bypeaks at 13.58, 13.98, 22.59, and 25.46 degrees on a 2-theta scale in anXRPD pattern. In another further embodiment, Form 26 is characterized bypeaks at 13.58, 13.98, 14.05, 22.59, 25.35, and 25.46 degrees on a2-theta scale in an XRPD pattern. In still a further embodiment, Form 26is characterized by an XRPD pattern according to FIG. 9. In anotherfurther embodiment, Form 26 is characterized by an XRPD pattern havingpeak values according to Table 28.

TABLE 28 Form 26 2θ Relative Intensity (%) 10.50 26.15 10.59 28.32 13.58100.00 13.98 47.54 14.05 37.72 18.71 27.02 21.01 30.19 22.59 45.50 23.2427.89 24.35 31.45 25.38 44.19 25.46 48.12 26.73 21.49 26.88 19.13 27.4021.45 27.96 16.13

In one aspect, the invention includes Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•isethionate monohydrate,characterized as Form 27, wherein the crystalline solid comprisesCompound 1 and isethionate in a 1:1 molar ratio. In one embodiment, Form27 is characterized by one or more peaks on a 2-theta scale in an XRPDpattern selected from the group consisting of 6.56, 12.39, 12.59, 13.14,16.57, 17.55, 21.68, 23.66, 24.33, 26.09, 26.53, 26.69, and 27.40degrees. In another embodiment, Form 27 is characterized by one or morepeaks on a 2-theta scale in an XRPD pattern selected from the groupconsisting of 12.39, 12.59, 17.55, 21.68, 23.66, and 26.09 degrees. In afurther embodiment, Form 27 is characterized by peaks at 12.39, 12.59,17.55, 21.68, 23.66, and 26.09 degrees on a 2-theta scale in an XRPDpattern. In a further embodiment, Form 27 is characterized by peaks at12.39, 12.59, 17.55, 21.68, 23.66, 24.33, and 26.09 degrees on a 2-thetascale in an XRPD pattern. In still a further embodiment, Form 27 ischaracterized by an XRPD pattern according to FIG. 9. In another furtherembodiment, Form 27 is characterized by an XRPD pattern having peakvalues according to Table 29.

TABLE 29 Form 27 2θ Relative Intensity (%) 6.56 42.00 12.39 100.00 12.5993.66 13.14 25.50 16.57 49.22 17.55 90.99 21.68 57.20 23.66 84.95 24.3361.05 26.09 65.46 26.53 42.97 26.69 35.13 27.40 29.37

In another aspect, the invention includes a pharmaceutical compositioncomprising a therapeutically effective amount of a substantially purecrystalline solid form of a salt of Compound 1 as described herein, anda pharmaceutically acceptable carrier.

In still another aspect, the invention includes a pharmaceuticalcomposition comprising a therapeutically effective amount of a mixtureof crystalline solid forms of a salt of Compound 1 as described herein,and a pharmaceutically acceptable carrier.

In another aspect, the invention includes a method of treating cancercomprising administering to a subject a therapeutically effective amountof a crystalline solid form of a salt of Compound 1 as described herein.

In still another aspect, the invention includes a method of treatingcancer comprising administering to a subject a pharmaceuticalcomposition as described herein.

In one embodiment of this aspect, the cancer is selected from thyroidcancer, stomach cancer, esophageal carcinoma, kidney cancer, livercancer, ovarian carcinoma, cervical carcinoma, large bowel cancer, smallbowel cancer, brain cancer, lung cancer, bone cancer, prostatecarcinoma, pancreatic carcinoma, skin cancer, bone cancer, lymphoma,solid tumors, Hodgkin's disease, or non-Hodgkin's lymphoma.

In a further embodiment, the thyroid cancer is medullary thyroid cancer.

In another further embodiment, the kidney cancer is renal cellcarcinoma.

In another embodiment, the liver cancer is heptatocellular carcinoma.

In another embodiment, the brain cancer is an astrocytic tumor.

In a further embodiment, the astrocytic tumor is selected from aglioblastoma, a giant cell glioblastoma, and a gliosarcoma.

In still a further embodiment, the glioblastoma possessesoligodendroglial components.

In one embodiment, the lung cancer is non-small cell lung cancer.

In another embodiment, the prostate carcinoma is castration resistantprostate cancer.

In another aspect, the invention includes a method of treating diseasesor disorders associated with uncontrolled, abnormal, and/or unwantedcellular activities due to cMET or RET overexpression, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of at least one solid form of Compound 1 as disclosedherein.

In still another aspect, the invention includes a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities due to cMET or RET overexpression,comprising administering to a subject in need of such treatment atherapeutically effective amount of a pharmaceutical composition asdisclosed herein.

Pharmaceutical Compositions and Methods of Treatment

Another aspect of this disclosure relates to a pharmaceuticalcomposition comprising at least one crystalline solid form of Compound 1as described herein in any of the aspects and/or embodiments, orcombinations thereof, and a pharmaceutically acceptable excipient.Pharmaceutical compositions of Compound 1 have been disclosed in, forexample, commonly assigned PCT Patent Publication Nos. WO 2005/030140,WO 2012/009722, and WO 2012/109510, each of which is incorporated byreference herein in its entirety.

The amount of the crystalline Compound 1 solid form or combinationsthereof in the pharmaceutical composition can be a therapeuticallyeffective amount. The crystalline solid forms of Compound 1 mayindividually be present in the pharmaceutical composition or ascombinations. The crystalline solid forms as disclosed herein includeForms 1-27. Accordingly, another aspect of this disclosure relates to asolid or dispersion pharmaceutical composition comprising at least oneof a therapeutically effective amount of a solid form of Compound 1, asdescribed herein in any of the aspects and/or embodiments, orcombinations thereof, and a pharmaceutically acceptable excipient.

A pharmaceutical composition such as disclosed herein may be anypharmaceutical form which contains an active crystalline Compound 1solid form. The pharmaceutical composition may be, for example, atablet, capsule, liquid suspension, injectable, topical, or transdermal.The pharmaceutical compositions generally contain about 1% to about 99%by weight of the active compound(s), or a solid form of the activecompound(s), and 99% to 1% by weight of a suitable pharmaceuticalexcipient. In one example, the composition will be between about 5% andabout 75% by weight of active compound, with the rest being suitablepharmaceutical excipients or other adjuvants, as discussed below.

The actual amount required for treatment of any particular subject willdepend upon a variety of factors, including the disease state beingtreated and its severity; the specific pharmaceutical compositionemployed; the age, body weight, general health, sex, and diet of thesubject; the mode of administration; the time of administration; theroute of administration; and the rate of excretion of the activecompound(s), or a solid form of the active compound(s), according tothis disclosure; the duration of the treatment; any drugs used incombination or coincidental with the specific compound employed; andother such factors well known in the medical arts. These factors arediscussed in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics,” Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference. The active compound(s), or a solid form of activecompound(s), according to this disclosure and pharmaceuticalcompositions comprising them, may be used in combination with anticanceror other agents that are generally administered to a subject beingtreated for cancer. They may also be co-formulated with one or more ofsuch agents in a single pharmaceutical composition.

Depending on the type of pharmaceutical composition, thepharmaceutically acceptable carrier may be chosen from any one or acombination of carriers known in the art. The choice of thepharmaceutically acceptable carrier depends partly upon the desiredmethod of administration to be used. For a pharmaceutical composition ofthis disclosure, that is, one of the active compound(s), or a solid formof the active compound(s), of this disclosure, a carrier should bechosen so as to substantially maintain the particular form of the activecompound(s), whether it would be solid or not. In other words, thecarrier should not substantially alter the form of the activecompound(s). Nor should the carrier be otherwise incompatible with theform of the active compound(s), such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutical composition.

Filler

As indicated above, the pharmaceutical composition containing Compound 1comprises a filler. Fillers are inert ingredients added to adjust thebulk in order to produce a size practical for compression. Examples offillers include sodium starch glycolate, corn starch, talc, sucrose,dextrose, glucose, lactose, xylitol, fructose, sorbitol, calciumphosphate, calcium sulfate, calcium carbonate, and the like, or mixturesthereof. Microcrystalline cellulose may also be used as a filler and maybe any suitable form of microcrystalline cellulose as is known and usedin the tabletting art. Preferably, a mixture of lactose andmicrocrystalline cellulose is used as the filler. In one embodiment, thelactose is anhydrous lactose sold as Lactose 60M, which is readilycommercially available from a number of suppliers. In one embodiment,the microcrystalline cellulose is Avicel PI-1-102, which is alsocommercially available.

Preferably, filler(s) are present in an amount of from about 50 to about70 percent, and more preferably from about 57 to about 67 percent, byweight on a solids basis of the directly compressible formulation.Preferably, lactose is present in an amount of from about 18 to 22percent by weight. Preferably, the microcrystalline cellulose is presentin an amount of from about 38 to 40 percent by weight.

Binder

The pharmaceutical composition containing Compound 1 also comprises abinder. Binders are added to powders to impart cohesive qualities to thepowder, which allows the compressed tablet to retain its integrity. Thebinder can be any pharmaceutically acceptable binder available in thetabletting art, such as acacia, alginic acid, carbomer,carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guargum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose,magnesium aluminium silicate, maltodextrin, methylcellulose,polymethacrylates, povidone, pregelatinized starch, sodium alginate,starch, zein, and the like, or mixtures thereof.

The preferred binder is hydroxypropyl cellulose preferably in an amountof from about 2 to about 4 percent by weight on a solid basis of thedirectly compressible formulation. In one embodiment, the hydroxypropylcellulose is commercially available Klucel EXF.

Disintegrant

The pharmaceutical composition containing Compound 1 also comprises adisintegrant. A disintegrant is a substance or a mixture of substancesadded to facilitate breakup or disintegrate after administration. Thedisintegrant may be any pharmaceutically acceptable disintegrantavailable in the tabletting art, including alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidalsilicon dioxide, croscarmellose sodium, crospovidone, guar gum,magnesium aluminum silicate, methylcellulose, microcrystallinecellulose, polyacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, starch, and the like, or mixtures thereof.

The preferred disintegrant is croscarmellose sodium, in an amount offrom about 4 to about 8 percent by weight, on a solid basis of thedirectly compressible formulation. In one embodiment, the croscarmellosesodium is commercially available Ac-Di-Sol.

Glidant

The pharmaceutical composition containing Compound 1 also comprises aglidant. The glidant may be any pharmaceutically acceptable glidantwhich contributes to the compressibility, flowability, and homogeneityof the formulation and which minimizes segregation and does notsignificantly interfere with the release mechanism of the binders as setforth above. Preferably, the glidant is selected to improve the flow ofthe formulation. Silicon dioxide, particularly colloidal silicondioxide, is preferred as a glidant.

The glidant is used in an amount of from about 0.2 to about 0.6 percentby weight on a solid basis of the directly compressible formulation.More particularly, silicon dioxide, particularly colloidal silicondioxide, is used in an amount of from about 0.2 to about 0.6 percent byweight on a solid basis of the directly compressible formulation.

Lubricant

The pharmaceutical composition containing Compound 1 also comprises alubricant. Lubricants are employed to prevent adhesion of the tabletmaterial to the surface of dyes and punches. The lubricant may be anypharmaceutically acceptable lubricant which substantially preventssegregation of the powder by contributing to homogeneity of theformulation and which exhibits good flowability. Preferably, thelubricant functions to facilitate compression of the tablets andejection of the tablets from the die cavity. Such lubricants may behydrophilic or hydrophobic, and examples include magnesium stearate,Lubritab®, stearic acid, talc, and other lubricants known in the art orto be developed which exhibit acceptable or comparable properties, ormixtures thereof. Examples of lubricants include calcium stearate,glyceryl monostearate, glyceryl palmitostearate, hydrogenated castoroil, hydrogenated vegetable oil, light mineral oil, magnesium stearate,mineral oil, polyethylene glycol, sodium benzoate, sodium laurylsulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, andthe like, or mixtures thereof.

The lubricant should be selected to aid in the flow of the powder in thehopper and into the die. Magnesium stearate exhibits excellentproperties in combination with the other preferred excipients of theformulation. Magnesium stearate contributes to reducing friction betweenthe die wall and tablet formulation during compression, as well as tothe easy ejection of the Compound 1 tablets. It also resists adhesion topunches and dies.

Preferably, the lubricant is magnesium stearate (non-bovine) used in anamount of from about 0.5 to about 1.0 percent by weight on a solid basisof the directly compressible formulation.

Film Coating

The pharmaceutical composition containing Compound 1 also comprises anoptional film coating. The film coat concentration can be about 1 toabout 10 percent by weight on a solid basis of the directly compressibleformulation. Film coating suspensions may include combinations of thefollowing components: hypromeollose, carboxymethylcellulose sodium,carnauba wax, cellulose acetate phthalate, cetyl alcohol, confectioner'ssugar, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, liquid glucose, maltodextrin,methyl cellulose, microcrystalline wax, Opadry and Opadry II,polymethacrylates, polyvinyl alcohol, shellac, sucrose, talc, titaniumdioxide, and zein.

Other Adjuvants

Other pharmaceutically acceptable adjuvants known in the pharmaceuticalformulation art may also be used in the pharmaceutical compositions ofthis disclosure. These include, but are not limited to, preserving,wetting, suspending, sweetening, flavoring, perfuming, emulsifying, anddispensing agents. Prevention of the action of microorganisms can beensured by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, and the like. It may alsobe desirable to include isotonic agents, for example sugars, sodiumchloride, and the like. If desired, a pharmaceutical composition of thisdisclosure may also contain minor amounts of auxiliary substances suchas wetting or emulsifying agents, pH buffering agents, and antioxidants,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, and butylated hydroxytoluene.

The pharmaceutical compositions of this disclosure may be prepared bymethods know in the pharmaceutical formulation art, for example, seeRemington's Pharmaceutical Sciences, 18^(th) Ed., (Mack PublishingCompany, Easton, Pa., 1990). In solid dosage forms, any one of Forms1-27, or combinations thereof, is admixed with at least onepharmaceutically acceptable excipient such as sodium citrate ordicalcium phosphate or (a) fillers or extenders, as for example,starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b)binders, as for example, cellulose derivatives, starch, alginates,gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants,as for example, glycerol, (d) disintegrating agents, as for example,agar-agar, calcium carbonate, potato or tapioca starch, alginic acid,croscarmellose sodium, complex silicates, and sodium carbonate, (e)solution retarders, as for example paraffin, (f) absorptionaccelerators, as for example, quaternary ammonium compounds, (g) wettingagents, as for example, cetyl alcohol, and glycerol monostearate,magnesium stearate, and the like (h) adsorbents, as for example, kaolinand bentonite, and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents.

In some instances, the pharmaceutical dosage form may be a soliddispersion. The term “solid dispersion” refers to a system in a solidstate comprising at least two components, wherein one component isdispersed throughout the other component or components. For example, thesolid dispersion can be an amorphous solid dispersion. The tem“amorphous solid dispersion,” as used herein, refers to stable soliddispersions comprising amorphous drug substance (Compound 1) and astabilizing polymer. By “amorphous drug substance,” it is meant that theamorphous solid dispersion contains a drug substance in a substantiallyamorphous solid form—that is at least 80% of the drug substance in thedispersion is in an amorphous form. More preferably, at least 90%, andmost preferably at least 95%, of the drug substance in the dispersion isin amorphous form. The term “stabilizing polymer” means any polymerknown to the skilled practitioner that is used to stabilize an amorphousdrug substance in a solid dispersion, such as those described, forinstance, in Remington's Pharmaceutical Sciences, 18^(th) Ed., (MackPublishing Company, Easton, Pa., 1990).

Processes for making such solid dispersions are also available to theskilled practitioner and include, for instance, spray drying, meltextrusion, freeze drying, rotary evaporation, drum drying, or othersolvent removal processes. In the spray drying process, the amorphousdispersion is formed by dispersing or dissolving the drug substance andthe stabilizing polymer in a suitable solvent to form a feed solution,pumping the feed solution through an atomizer into a drying chamber, andremoving the solvent to form the amorphous solid dispersion powder inthe drying chamber. A drying chamber uses hot gases, such as forced air,nitrogen, nitrogen-enriched air, or argon to dry particles. The feedsolution can be atomized by conventional means well known in the art,such as a two-fluid sonicating nozzle and a two-fluid non-sonicatingnozzle.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the active compound(s), or a solid formof the active compound(s), with, for example, suitable non-irritatingexcipients or carriers such as cocoa butter, polyethyleneglycol, or asuppository wax, which are solid at ordinary temperatures but liquid atbody temperature and therefore melt while in a suitable body cavity andrelease the active component therein.

Solid dosage forms are preferred for the pharmaceutical composition ofthis disclosure. Solid dosage forms for oral administration, whichincludes capsules, tablets, pills, powders, and granules, areparticularly preferred. In such solid dosage forms, the activecompound(s) mixed with at least one inert, pharmaceutically acceptableexcipient (also known as a pharmaceutically acceptable carrier).Administration of the active compound(s), or a solid form of the activecompound(s), in pure form or in an appropriate pharmaceuticalcomposition, can be carried out via any of the accepted modes ofadministration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, and aerosols,and the like, preferably in unit dosage forms suitable for simpleadministration of precise dosages. One preferable route ofadministration is oral administration, using a convenient dosage regimenthat can be adjusted according to the degree of severity of thedisease-state to be treated. For example, the dosage regimen can be as acapsule or tablet for oral administration.

The skilled artisan will recognize that a greater amount of Compound 1as one of the salt forms described herein is present to provide acertain amount of Compound 1. For example, the molecular weight ofCompound 1 is 501.51, and the molecular weight of Compound 1, pyruvatesalt is 589.56. Thus, 117.56 mg of Compound 1, pyruvate salt is requiredis required to provide 100 mg of Compound 1. The “free base equivalent”(the) of a tablet containing 117.56 mg of Compound 1, pyruvate is 100 mgCompound 1. Proportionally smaller or larger amounts of Compound 1L-malate salt are required for tablet compositions containing less ormore of Compound 1.

In another aspect, the disclosure relates to a pharmaceuticalcomposition comprising a Compound 1 in at least one of forms disclosedherein and a pharmaceutically acceptable carrier containing less than100 ppm of 6,7-dimethoxy-quinoline-4-ol. 6,7-dimethoxy-quinoline-4-ol,the structure of which is

Minimizing the concentration of degradation products, contaminants, orbyproducts such as 6,7-dimethoxy-quinoline-4-ol in pharmaceuticalcompositions destined for human administration is desirable. In oneembodiment, a pharmaceutical composition comprising a Compound 1 in atleast one of forms disclosed herein and a pharmaceutically acceptablecarrier containing less than 90 ppm, less than 80 ppm, less than 70 ppm,less than 60 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm,less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 2.5ppm of 6,7-dimethoxy-quinoline-4-ol. 6,7-dimethoxy-quinoline-4-ol, thestructure of which is

In another aspect, a pharmaceutical composition comprising a Compound 1in at least one of forms disclosed herein and a pharmaceuticallyacceptable carrier containing 1 to 100 ppm, 1 to 80 ppm, 1 to 60 ppm, 1to 40 ppm, 1 to 20 ppm, 1 to 10 ppm, 1 to 5 ppm, or 1 to 2.5 ppm of6,7-dimethoxy-quinoline-4-ol. 6,7-dimethoxy-quinoline-4-ol, thestructure of which is

In another aspect, a pharmaceutical composition comprising a Compound 1in at least one of forms disclosed herein and a pharmaceuticallyacceptable carrier containing 0.1 to 100 ppm, 0.1 to 80 ppm, 0.1 to 60ppm, 0.1 to 40 ppm, 0.1 to 20 ppm, 0.1 to 10 ppm, 0.1 to 5 ppm, 0.1 to2.5 ppm, or 0.1 to 1 ppm of 6,7-dimethoxy-quinoline-4-ol.6,7-dimethoxy-quinoline-4-ol, the structure of which is

Capsule Formulation

In one embodiment, the dosage regimen is as a capsule formulation fororal administration.

In one embodiment, the capsule formulation comprises:

-   -   5-60 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   30-80 percent by weight of one or more fillers;    -   1-15 percent by weight of one or more disintegrants;    -   0.1 to 1.0 percent by weight of a glidant; and    -   0.1 to 4.0 percent by weight of a lubricant.

In another embodiment, the capsule formulation comprises:

-   -   5-60 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   30-80 percent by weight of one or more fillers;    -   2-12 percent by weight of one or more disintegrants;    -   0.1 to 0.6 percent by weight of a glidant; and    -   0.1 to 3.0 percent by weight of a lubricant.

In another embodiment, the capsule formulation comprises:

-   -   5-15 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   70-80 percent by weight of one or more fillers;    -   8-12 percent by weight of one or more disintegrants;    -   0.1 to 0.4 percent by weight of a glidant; and    -   0.1 to 2.0 percent by weight of a lubricant.

In another embodiment, the capsule formulation comprises:

-   -   5-15 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   70-80 percent by weight of one or more fillers;    -   9-11 percent by weight of one or more disintegrants;    -   0.2 to 0.4 percent by weight of a glidant; and    -   0.5 to 1.5 percent by weight of a lubricant.

In another embodiment, the capsule formulation comprises:

-   -   40-60 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   30-50 percent by weight of one or more fillers;    -   2-12 percent by weight of one or more disintegrants;    -   0.1 to 0.6 percent by weight of a glidant; and    -   0.1 to 3.0 percent by weight of a lubricant.

In another embodiment, the capsule formulation comprises:

-   -   45-55 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   35-40 percent by weight of one or more fillers;    -   8-12 percent by weight of one or more disintegrants;    -   0.2 to 0.5 percent by weight of a glidant; and    -   0.5 to 2.5 percent by weight of a lubricant.

In another embodiment, the capsule formulation comprises:

-   -   5-60 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   30-80 percent by weight of microcrystalline cellulose;    -   2-7 percent by weight of croscarmellose sodium;    -   2-7 percent by weight of sodium starch glycolate;    -   0.1 to 1.0 percent by weight of a fumed silica; and    -   0.1 to 4.0 percent by weight of stearic acid.

In another embodiment, the capsule formulation comprises:

-   -   5-60 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   30-80 percent by weight of microcrystalline cellulose;    -   3-6 percent by weight of croscarmellose sodium;    -   3-6 percent by weight of sodium starch glycolate;    -   0.1 to 0.6 percent by weight of fumed silica; and    -   0.1 to 3.0 percent by weight of stearic acid.

In another embodiment, the capsule formulation comprises:

-   -   5-15 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   70-80 percent by weight of microcrystalline cellulose;    -   4-6 percent by weight of croscarmellose sodium;    -   4-6 percent by weight of sodium starch glycolate;    -   0.1 to 0.4 percent by weight of fumed silica; and    -   0.1 to 2.0 percent by weight of stearic acid.

In another embodiment, the capsule formulation comprises:

-   -   5-15 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   70-80 percent by weight of microcrystalline cellulose;    -   4.5-5.5 percent by weight of croscarmellose sodium;    -   4.5-5.5 percent by weight of sodium starch glycolate;    -   0.2 to 0.4 percent by weight of fumed silica; and    -   0.5 to 1.5 percent by weight of stearic acid.

In another embodiment, the capsule formulation comprises:

-   -   40-60 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   30-50 percent by weight of microcrystalline cellulose;    -   2-7 percent by weight of croscarmellose sodium;    -   2-7 percent by weight of sodium starch glycolate;    -   0.1 to 0.6 percent by weight of fumed silica; and    -   0.1 to 3.0 percent by weight of stearic acid.

In another embodiment, the capsule formulation comprises:

-   -   45-55 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   35-40 percent by weight of microcrystalline cellulose;    -   3-6 percent by weight of croscarmellose sodium;    -   3-6 percent by weight of sodium starch glycolate;    -   0.2 to 0.5 percent by weight of fumed silica; and    -   0.5 to 2.5 percent by weight of stearic acid.

In one embodiment, the capsule compositions of this disclosure containfrom 5 to about 200 mg of Compound 1 in at least one of the formsdescribed herein. In another embodiment, the capsule compositions ofthis disclosure contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140,145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg ofCompound 1. In another embodiment, the capsule compositions of thisdisclosure contain from 105 to 200 mg of Compound 1. In anotherembodiment, the capsule compositions of this disclosure contain 105,110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175,180, 185, 190, 195, or 200 mg of Compound 1. In another embodiment, thecapsule compositions of this disclosure contain from 20 to 100 mg ofCompound 1. In another embodiment, the capsule compositions of thisdisclosure contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, 90, 95, or 100 mg of Compound 1. In another embodiment,the capsule compositions of this disclosure contain from 20 to 60 mg ofCompound 1. In another embodiment, the capsule compositions of thisdisclosure contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mgof Compound 1. In another embodiment, the capsule compositions contain20, 25, 40, 50, 60, 75, 80, or 100 mg of Compound 1. In anotherembodiment, the capsule compositions of this disclosure contain 20 mg ofCompound 1. In another embodiment, the capsule compositions of thisdisclosure contain 40 mg of Compound 1. In another embodiment, thecapsule compositions of this disclosure contain 60 mg of Compound 1. Inanother embodiment, the capsule compositions of this disclosure contain80 mg of Compound 1.

In another aspect, the disclosure provides a pharmaceutical capsulecomposition according to Table 30.

TABLE 30 Ingredient mg/unit dose Compound 1 (As one or 25 more of Forms1-27 (based on free base)) Silicified Microcrystalline 196.75 CelluloseCroscarmellose sodium 12.5 Sodium starch glycolate 12.5 Fumed Silica0.75 Stearic acid 2.5 Total Fill Weight 250

In another aspect, the disclosure provides a pharmaceutical capsulecomposition according to Table 31.

TABLE 31 Ingredient mg/unit dose Compound 1 (As one or 100 more of Forms1-27 (based on free base)) Silicified Microcrystalline 75.40 CelluloseCroscarmellose sodium 10.00 Sodium Starch Glycolate 10.00 Fumed silica0.6 Stearic Acid 4.0 Total Fill Weight 200

The capsule formulations can be prepared according to methods availableto the skilled person, by combining and mixing the components of theformulation and filling two-piece hard gelatin capsules. The capsuleshell ingredients include gelatin and optionally colorant.

Tablet Formulation

In one embodiment, the dosage regimen is as a tablet formulation fororal administration.

In one embodiment, the tablet formulation comprises:

-   -   25-40 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   45-75 percent by weight of one or more diluents;    -   1-5 percent by weight of a binder;    -   2-10 percent by weight a disintegrant; and    -   0.05-1.0 percent by weight of a glidant;    -   and 0.5-1 percent by weight of a lubricant.

In another embodiment, the tablet composition comprises

-   -   28-38 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   48-68 percent by weight of one or more diluents;    -   1.5-4.5 percent by weight of a binder;    -   3-9 percent by weight a disintegrant; and    -   0.1-0.8 percent by weight of a glidant;    -   and 0.5-1 percent by weight of a lubricant.

In another embodiment, the tablet composition comprises

-   -   28-38 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   48-68 percent by weight of one or more diluents;    -   1.5-4.5 percent by weight of a binder;    -   3-9 percent by weight a disintegrant; and    -   0.1-0.8 percent by weight of a glidant;    -   and 0.5-1 percent by weight of a lubricant.

In another embodiment, the tablet composition comprises:

-   -   30-32 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   50-70 percent by weight of one or more diluents;    -   2-4 percent by weight of a binder;    -   4-8 percent by weight a disintegrant; and    -   0.2-0.6 percent by weight of a glidant;    -   and 0.5-1 percent by weight of a lubricant; wherein the        composition is coated.

In another embodiment, the tablet formulation comprises:

-   -   25-40 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   35-45 percent by weight or microcrystalline cellulose;    -   15 to 25 percent by weight of lactose anhydrous;    -   1-5 percent by weight of hydroxypropyl cellulose;    -   2-10 percent by weight croscarmellose sodium;    -   0.05-1.0 percent by weight of a colloidal silicon dioxide; and    -   0.5-1 percent by weight magnesium stearate.

In another embodiment, the tablet composition comprises

-   -   28-38 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   36-42 percent by weight or microcrystalline cellulose;    -   18 to 22 percent by weight of lactose anhydrous;    -   1.5-4.5 percent by weight of a hydroxypropyl cellulose;    -   3-9 percent by weight a croscarmellose sodium; and    -   0.1-0.8 percent by weight of a colloidal silicon disoxide; and    -   0.5-1 percent by weight of a magnesium stearate.

In another embodiment, the tablet composition comprises

-   -   28-38 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   37-39 percent by weight or microcrystalline cellulose;    -   18 to 20 percent by weight of lactose anhydrous;    -   1.5-4.5 percent by weight of hydroxypropyl cellulose;    -   3-9 percent by weight a croscarmellose sodium; and    -   0.1-0.8 percent by weight of colloidal silicon dioxide; and    -   0.5-1 percent by weight of magnesium stearate.

In another embodiment, the tablet composition comprises:

-   -   30-32 percent by weight of Compound 1 in at least one of the        forms disclosed herein;    -   38-39 percent by weight or microcrystalline cellulose;    -   19 to 20 percent by weight of lactose anhydrous;    -   2-4 percent by weight of hydroxypropyl cellulose;    -   4-8 percent by weight a croscarmellose sodium; and    -   0.2-0.6 percent by weight of colloidal silicon dioxide; and    -   0.5-1 percent by weight of a magnesium stearate.

The tablet formulations of these and other embodiments can be coated.Many coatings are known to the skilled person. An example of a coatingis OPADRY Yellow, which contains hypromellose, titanium dioxide,triacetin, and iron oxide yellow.

In one embodiment, the tablet compositions of this disclosure containfrom 5 to about 200 mg of Compound 1 in at least one of the formsdescribed herein. In another embodiment, the tablet compositions of thisdisclosure contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140,145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg ofCompound 1. In another embodiment, the tablet compositions of thisdisclosure contain from 105 to 200 mg of Compound 1. In anotherembodiment, the tablet compositions of this disclosure contain 105, 110,115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180,185, 190, 195, or 200 mg of Compound 1. In another embodiment, thetablet compositions of this disclosure contain from 20 to 100 mg ofCompound 1. In another embodiment, the tablet compositions of thisdisclosure contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, 90, 95, or 100 mg of Compound 1. In another embodiment,the tablet compositions of this disclosure contain from 20 to 60 mg ofCompound 1. In another embodiment, the tablet compositions of thisdisclosure contain 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mgof Compound 1. In another embodiment, the tablet compositions contain20, 25, 40, 50, 60, 75, 80, or 100 mg of Compound 1. In anotherembodiment, the tablet compositions of this disclosure contain 20 mg ofCompound 1. In another embodiment, the tablet compositions of thisdisclosure contain 40 mg of Compound 1. In another embodiment, thetablet compositions of this disclosure contain 60 mg of Compound 1.

In another embodiment, the once-daily tablet comprises:

Ingredient (% w/w) Compound 1 (As one or more of Forms 31.68 1-27 (basedon free base)) Microcrystalline Cellulose 38.85 Lactose anhydrous 19.42Hydroxypropyl Cellulose 3.00 Croscarmellose Sodium 3.00 TotalIntra-granular 95.95 Silicon dioxide, Colloidal 0.30 Croscarmello seSodium 3.00 Magnesium Stearate 0.75 Total 100.00

In another embodiment, the once-daily tablet formulation comprises:

Ingredient (% w/w) Compound 1 (As one or more of Forms 25.0-33.3 1-27(based on free base)) Microcrystalline Cellulose q.s HydroxypropylCellulose 3 Poloxamer 0-3 Croscarmellose Sodium 6.0 Colloidal SiliconDioxide 0.5 Magnesium Stearate 0.5-1.0 Total 100

In another embodiment, the once-daily tablet or capsule formulationcomprises:

Theoretical Quantity Ingredient (mg/unit dose) Compound 1 (As one ormore of 100.0 Forms 1-27 (based on free base)) MicrocrystallineCellulose PH-102 155.4 Lactose Anhydrous 60M 77.7 HydroxypropylCellulose, EXF 12.0 Croscarmellose Sodium 24 Colloidal Silicon Dioxide1.2 Magnesium Stearate (Non-Bovine) 3.0 Opadry Yellow 16.0 Total 416

In another embodiment, the once-daily tablet or capsule formulationcomprises:

Ingredient % w/w Compound 1 (As one or more of Forms 1-27 31.7 (based onfree base)) Microcrystalline Cellulose (Avicel PH-102) 38.9 LactoseAnhydrous (60M) 19.4 Hydroxypropyl Cellulose (EXF) 3.0 CroscarmelloseSodium (Ac-Di-Sol) 6.0 Colloidal Silicon Dioxide 0.3 Magnesium Stearate0.75 Opadry Yellow Film Coating which includes: 4.00 HPMC2910/Hypromellose 6 cp Titanium dioxide Triacetin Iron Oxide Yellow

This disclosure is also directed to a process for making the tabletpharmaceutical formulations comprising Compound 1 as one of the saltsdisclosed herein.

In an embodiment, the process for making the tablet formulationcomprises mixing Compound 1 with one or more of the pharmaceuticalexcipients. The mixture is then taken up in an aqueous solutioncontaining a binder to form a binder solution. The binder solution isgranulated using a granulation technique known in the art. For example,the granulation method may comprise wet high shear granulation using awet high shear granulator. The resulting wet granules are then screenedand dried using fluid bed drying or the like. The dried granules arethen milled. The resulting dry milled granules are then mixed with aglidant and a disintegrant to form an extra-granular blend. A lubricantis then blended into the extraganular blend to form the final blend. Thefinal blend is subsequently compressed to form the compressed tablet,which may be film coated.

More particularly, the process for making the tablet formulationcomprises delumping Compound 1 as needed prior to mixing with theexcipients. Delumping ensures that the Compound 1 mixes homogeneouslywith the other excipients during the formulation process. DelumpedCompound 1 is then mixed with microcrystalline cellulose, such as AvicelPH102, lactose (anhydrous, 60M), and croscarmellose sodium. This mixtureis then combined with EXF grade hydroxypropoyl cellulose in water toform a binder solution, which is then wet high shear granulated. Theresulting wet granules are wet screened and then fluid bed driedaccording to methods available to the skilled artisan. The resultingdried granules are milled and combined with colloidal silicon dioxideand croscarmellose sodium. Magnesium stearate is added to the mixture.This final blend is then ready for tablet compression. The resultinguncoated core tablets are subsequently film coated. The film coatingcomprises Opadry Yellow, which contains hypromellose, titanium dioxide,triacetin, and iron oxide yellow.

More particularly, the formulation process comprises:

-   -   a) Delumping unmilled Compound 1;    -   b) Premixing the delumped Compound 1 with Avicel PH102, lactose        anhydrous 60M, and croscarmellose sodium to form a binder        solution;    -   c) Wet high shear granulation of the binder solution to produce        wet granules;    -   d) Wet screening of the wet granules to produce wet screened        granules;    -   e) Fluid bed drying of the wet screened granules to produce        dried granules;    -   f) Dry milling of the dried granules to produce dried milled        granules;    -   g) Blending the dried milled granules with colloidal silicon and        croscarmellose to produce an extragranular blend;    -   h) Lubricant blending of the extragranular blend and magnesium        stearate to produce a final blend;    -   i) Tablet compression of the final blend to form an uncoated        core tablet; and    -   j) Film coating of the uncoated core tablet.

Treatment Methods

Another aspect of this disclosure relates to a method of treating cancercomprising administering to a subject in need thereof at least one ofsolid form of Compound 1 as described herein in any of the aspectsand/or embodiments, or combinations thereof. Methods of treatmentcomprising administering Compound 1 have been disclosed in, for example,commonly assigned PCT Patent Publication Nos. WO 2005/030140, WO2011/017639, WO 2012/044572, WO 2012/044577, WO 2012/151326, WO2013/043840, WO 2013/070890, WO 2013/070903, and WO2013/066296, and USPatent Application Publication Nos. US 2012/0070368 and US 2012/0252840,each of which is incorporated by reference herein in its entirety. Theamount of the Compound 1 solid form or combinations thereof administeredcan be a therapeutically effective amount.

Another aspect of this disclosure relates to a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities associated with RTK overexpression,particularly cMET of RET overexpression, comprising administering to asubject in need of such treatment a therapeutically effective amount ofat least one solid form of Compound 1 as described herein in any of theaspects and/or embodiments, or combinations thereof, such as discussedabove.

Another aspect of this disclosure relates to a use of solid Compound 1according to any of the above embodiments for the manufacture of amedicament for the treatment of a disease or disorder discussed above.When dissolved, a solid or amorphous form according to this disclosureloses its solid state structure, and is therefore referred to as asolution of, for example, Compound 1. At least one solid form disclosedherein may be used to prepare at least one liquid formulation in whichat least one solid form according to the disclosure is dissolved and/orsuspended.

In another aspect, the invention is directed to a method of treatingcancer, comprising: administering a pharmaceutical dosage formcomprising one or more of Forms 1-27 or a pharmaceutical compositioncomprising one or more of Forms 1-27 and a pharmaceutically acceptablecarrier.

In one embodiment of this aspect, the invention is directed to a methodof treating cancer, comprising administering to a patient in need ofsuch treatment a pharmaceutical dosage form comprising Compound 1 as oneor more Forms 1-27 as a pharmaceutical dosage from described herein. Insome embodiments, the dosage form is administered orally with fastingorally once daily as a tablet or capsule. In some embodiments, one ormore of Forms 1-27 or a pharmaceutical composition comprising one ormore of Forms 1-27 is administered as a tablet. In other embodiments,one or more of Forms 1-27 or a pharmaceutical composition comprising oneor more of Forms 1-27 is administered as a capsule.

Any of the tablet or capsule formulations provided above can be adjustedaccording to the dose of Compound 1 desired. Thus, the amount of each ofthe formulation ingredients can be proportionally adjusted to provide atable formulation containing various amounts of Compound 1 as providedin the previous paragraphs. In another embodiment, the formulations cancontain 20, 40, 60, or 80 mg free base equivalent of one or more ofForms 1-27.

In this method, the desired dosage of Compound 1 os one or more of Forms1-27 as described herein can be achieved using a combination of tabletsor capsules as needed. For example, to achieve a target dose of 20 mgwould require administration of one 20 mg free base equivalent tablet orcapsule. To achieve a target dose of 100 mg free base equivalent wouldrequire administration of one 80 mg free base equivalent tablet orcapsule and one 20 mg free base equivalent tablet or capsule. To achievea target dose of 80 mg free base equivalent would require administrationof one 80 mg free base equivalent tablet or capsule. To achieve a targetdose of 60 mg free base equivalent would require administration of three20 mg free base equivalent tablets or capsules.

In another embodiment of this method, 60 mg free base equivalent ofCompound 1 is administered once daily to a patient with cancer in needof treatment. To achieve a dose of 60 mg free base equivalent ofCompound 1, a patient is administered three 20 mg free base equivalenttablets. The three 20 mg free base equivalent tablets can be taken atthe same time or sequentially. In a further embodiment, Compound 1 isorally administered with fasting (that is, without eating) forapproximately two hours before and 1 hour after administration. Compound1 is preferably administered with a glass of water (approximately 8ounces/240 mL).

In another embodiment of this method, 40 mg free base equivalent ofCompound 1 is administered once daily to a patient with cancer in needof treatment. To achieve a dose of 40 mg free base equivalent ofCompound 1, a patient is administered two 20 free base equivalent mgtablets. The two 20 mg free base equivalent tablets can be taken at thesame time or sequentially. In a further embodiment, Compound 1 as one ofthe crystalline solid forms disclosed herein (that is, one or more ofForms 1-27) is orally administered with fasting (that is, withouteating) for approximately two hours before and 1 hour afteradministration. Compound 1 is preferably administered with a glass ofwater (approximately 8 ounces/240 mL).

In another embodiment of this method, 20 mg free base equivalent ofCompound 1 is administered once daily to a patient with cancer in needof treatment. To achieve a dose of 20 mg free base equivalent ofCompound 1, a patient is administered one 20 mg free base equivalenttablet. In a further embodiment, Compound 1 is orally administered withfasting (that is, without eating) for approximately two hours before and1 hour after administration. Compound 1 is preferably administered witha glass of water (approximately 8 ounces/240 mL).

In another embodiment, the method comprises administering one or more ofForms 1-27 orally once daily as a tablet or capsule.

In another embodiment, the method comprises administering one or more ofForms 1-27 orally once daily as a capsule as provided in the followingtable:

In another embodiment, the method comprises administering one or more ofForms 1-27 orally once daily as a tablet as provided in the followingtable:

Ingredient (% w/w) Compound 1 (As one or more of Forms 31.68 1-27 (basedon free base)) Microcrystalline Cellulose 38.85 Lactose anhydrous 19.42Hydroxypropyl Cellulose 3.00 Croscarmellose Sodium 3.00 TotalIntra-granular 95.95 Silicon dioxide, Colloidal 0.30 CroscarmelloseSodium 3.00 Magnesium Stearate 0.75 Total 100.00

In another embodiment, the method comprises administering one or more ofForms 1-27 orally once daily as a tablet as provided in the followingtable:

Ingredient (% w/w) Compound 1 (As one or more of Forms 25.0-33.3 1-27(based on free base)) Microcrystalline Cellulose q.s HydroxypropylCellulose 3 Poloxamer 0-3 Croscarmellose Sodium 6.0 Colloidal SiliconDioxide 0.5 Magnesium Stearate 0.5-1.0 Total 100

In another embodiment, the method comprises administering one or more ofForms 1-27 orally once daily as a tablet as provided in the followingtable:

Theoretical Quantity Ingredient (mg/unit dose) Compound 1 (As one ormore of 100.0 Forms 1-27 (based on free base)) MicrocrystallineCellulose PH-102 155.4 Lactose Anhydrous 60M 77.7 HydroxypropylCellulose, EXF 12.0 Croscarmellose Sodium 24 Colloidal Silicon Dioxide1.2 Magnesium Stearate (Non-Bovine) 3.0 Opadry Yellow 16.0 Total 416

In another embodiment, the method comprises administering one or more ofForms 1-27 orally once daily as a tablet as provided in the followingtable:

Ingredient % w/w Compound 1 (As one or more of 31.7 Forms 1-27 (based onfree base)) Microcrystalline Cellulose (Avicel PH-102) 38.9 LactoseAnhydrous (60M) 19.4 Hydroxypropyl Cellulose (EXF) 3.0 CroscarmelloseSodium (Ac-Di-Sol) 6.0 Colloidal Silicon Dioxide 0.3 Magnesium Stearate0.75 Opadry Yellow Film Coating which includes: 4.00 HPMC2910/Hypromellose 6 cp Titanium dioxide Triacetin Iron Oxide Yellow

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [neplrroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defornians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal lands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

In one embodiment, the cancer being treated is selected from stomachcancer, esophageal carcinoma, kidney cancer, liver cancer, bladdercancer, ovarian carcinoma, cervical carcinoma, large bowel cancer, smallbowel cancer, brain cancer (including astrocytic tumor, which includesglioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastomawith oligodendroglial components), lung cancer (including non-small celllung cancer), bone cancer, prostate carcinoma, pancreatic carcinoma,skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease,non-Hodgkin's lymphoma, or thyroid cancer (including medullary thyroidcancer). More particularly, the cancer is pancreatic cancer,hepatocellular carcinoma (HCC), renal cell carcinoma,castration-resistant prostate cancer (CRPC), gastric or gastroesophagealjunction cancer, melanoma, small cell lung cancer (SCLC), ovariancancer, primary peritoneal or fallopian tube carcinoma, estrogenreceptor positive breast cancer, estrogen receptor/progesteronereceptor/HER2-negative (triple-negative) breast cancer, inflammatory(regardless of receptor status) breast cancer, non-small cell lungcancer (NSCLC), or medullary thyroid cancer.

Another aspect of this disclosure relates to a method of treating anastrocytic tumor (which includes glioblastoma, giant cell glioblastoma,gliosarcoma, and glioblastoma with oligodendroglial components)comprising administering to the subject in need of the treatment atherapeutically effective amount of Compound 1 in at least one of theforms described herein, pharmaceutically formulated as described herein.

Another aspect of this disclosure relates to a method of treatingthyroid cancer (including medullary thyroid cancer) comprisingadministering to the subject in need of the treatment a therapeuticallyeffective amount of Compound 1 in at least one of the forms describedherein, pharmaceutically formulated as described herein.

Another aspect of this disclosure relates to a method of treatinghepatocellular carcinoma comprising administering to the subject in needof the treatment a therapeutically effective amount of Compound 1 in atleast one of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treating renalcell carcinoma comprising administering to the subject in need of thetreatment a therapeutically effective amount of Compound 1 in at leastone of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treatingcastration resistant prostate cancer comprising administering to thesubject in need of the treatment a therapeutically effective amount ofCompound 1 in at least one of the forms described herein,pharmaceutically formulated as described herein. The amount administeredcan be a therapeutically effective amount.

Another aspect of this disclosure relates to a method of breast cancercomprising administering to the subject in need of the treatment atherapeutically effective amount of Compound 1 in at least one of theforms described herein, pharmaceutically formulated as described herein.

Another aspect of this disclosure relates to a method of treatingovarian cancer comprising administering to the subject in need of thetreatment a therapeutically effective amount of Compound 1 in at leastone of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treatingbladder cancer comprising administering to the subject in need of thetreatment a therapeutically effective amount of Compound 1 in at leastone of the forms described herein, pharmaceutically formulated asdescribed herein.

Another aspect of this disclosure relates to a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities. The method comprises administering to thesubject in need of the treatment a therapeutically effective amount ofCompound 1 in at least one of the forms described herein,pharmaceutically formulated as described herein.

In one embodiment, the cancer is thyroid cancer.

More particularly, the thyroid cancer is medullary thyroid cancer.

In one embodiment, the cancer in liver cancer.

More particularly, the liver cancer is hepatocellular carcinoma,cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, or hemagioma.

In one embodiment, the cancer is gastrointestinal cancer.

More particularly, the gastrointestinal cancer is cancer of theesophagus which is squamous cell carcinoma, adenocarcinoma, orleiomyosarcoma; cancer of the stomach which is carcinoma, or lymphoma;cancer of the pancreas, which is ductal adenocarcinoma, insulinoma,gucagonoma, gastrinoma, carcinoid tumors, or vipoma; cancer of the smallbowel, which is adenocarcinoma, lymphoma, carcinoid tumors, Karposi'ssarcoma, leiomyoma, hemagioma, lipoma; or cancer of the large bowel,which is adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, orleiomyoma.

In one embodiment, the cancer is cancer of the pancreas.

More particularly, the cancer of the pancreas is ductal adenocarcinoma,insulinoma, gucagonoma, gastrinoma, carcinoid tumors, or vipoma.

In another embodiment, the cancer is bladder cancer. In a furtherembodiment, the bladder cancer is squamous cell carcinoma, transitionalcell carcinoma, or adenocarcinoma.

In one embodiment, the cancer is bone cancer.

More particularly, the bone cancer is osteosarcoma, fibrosarcoma,malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma,malignant reticulum cell sarcoma, malignant giant cell tumor chordoma,osteocartiliginous exostoses, chondroblastoma, chondromyofibroma, orosteoid osteoma.

In one embodiment, the cancer is hematologic cancer.

More particularly, the hematologic cancer is myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, or myelodysplastic syndrome.

In one embodiment, the cancer is skin cancer.

More particularly, the skin cancer is malignant melanoma, basal cellcarcinoma, squamous cell carcinoma, or Karposi's sarcoma.

In one embodiment, the cancer is renal cancer.

More particularly, the renal cancer is a renal tumor.

In one embodiment, the cancer is breast cancer.

More particularly, the breast cancer is a breast tumor.

In one embodiment, the cancer is colon cancer.

More particularly, the colon cancer is a colon cancer tumor.

In one embodiment, the cancer is fallopian tube cancer.

More particularly, the fallopian tube cancer is fallopian tubecarcinoma.

In one embodiment, the cancer is ovarian cancer.

More particularly, the ovarian cancer is ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, or melanoma.

In another embodiment, the cancer is prostate cancer.

More particularly, the prostate cancer is adenocarcinoma or sarcoma.

In another embodiment, the prostate cancer is castration resistantprostate cancer (CRPC).

In another embodiment, the cancer is lung cancer.

More particularly, the lung cancer is bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hanlartoma, or inesothelioma.

Another aspect of this disclosure relates to a method of treating cancercomprising administering to the subject in need of the treatment atherapeutically effective amount of Compound 1 in at least one of theforms described herein, pharmaceutically formulated as described herein,optionally in combination with another agent. The method of treatmentmay be practiced by administering a tablet formulation of at Compound 1in at least one of the forms described herein, pharmaceuticallyformulated as described herein.

The antitumor effect of the dosage form of the compound as apharmaceutically acceptable salt is measured using serological and/orradiographic methods available to the skilled practitioner. Forserological methods, the relative concentration of a cancer biomarker ismeasured before and after administration of one or more of Forms 1-27. Apositive response means that there is a lower serological concentrationof the biomarker after treatment as compared to the concentration beforetreatment.

Complete Serological Response: Marker level less than 0.2 ng/mL measuredfor 2 consecutive measurements at least 4 weeks apart.

Serological Partial Response (PR): Decline of marker value, referencedto the pre-study level, by greater than or equal to 50% for 2consecutive measurements at least 2 weeks apart.

Stable Disease: Patients who do not meet the criteria for response (CRor PR) or serological progression.

Serological Progression (PD): Serological progression is observed whenthe marker level demonstrates an increase that is more than 50% ofnadir, taking as reference the lowest recorded marker level sincestarting therapy. Two consecutive increases must be documented with eachmeasurement obtained at least 2 weeks apart. On occasions, there may bean intermediate fluctuant value. In accordance with the Recommendationsof Cancer Clinical Trials Working Group, this will not restart theevaluation period so long as the intermediate value was not below theprevious nadir. These serological response levels can be modified asneeded based on the biomarker at issue.

In one embodiment, a complete serological response is observed inpatients being treated with the dosage form. In another embodiment, aserological partial response is observed in patients being treated withthe dosage form. In a further embodiment, stable disease is observed inpatients being treated with the dosage form.

With respect to radiographic methods, radiographic disease progressionis defined by RECIST 1.1 for soft tissue disease, or the appearance oftwo or more new bone lesions on bone scan. Progression in the absence ofclear symptomatic worsening at the first scheduled reassessment aftercommencement of treatment requires a confirmatory scan at later point intime. Standard imaging procedures available to the skilled practitioner,including technetium bone scans and CT scans, can be used to measureradiographic effect. Other radiographic methods such as NaF and FDG-PETmay also be used to measure radiographic effect.

As indicated previously, the amount of one or more of Forms 1-27 that isadministered as free base equivalent can be adjusted to avoid adverseevents. For example, in one embodiment, a pharmaceutical dosagecomprising 60 mg free base equivalent of one or more of Forms 1-27 isadministered to a patient that had one or more adverse events at adosage greater than 60 mg.

In another embodiments, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a pharmaceutical dosage between 80 mg and 160 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 70 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 80 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevent at a dosage of 90 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 100 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 110 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 120 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 130 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 140 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 150 mg.

In another embodiment, 60 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 160 mg.

In other embodiments, 60 mg free base equivalent of one or more of Forms1-27 is administered to a patient that had one or more adverse events ata pharmaceutical dosage of 140 mg or 100 mg free base equivalent.

In another embodiment, the pharmaceutical dosage comprising 40 mg freebase equivalent of one or more of Forms 1-27 is administered to apatient that had one or more adverse events at a dosage greater than 40mg.

In another, 40 mg free base equivalent of one or more of Forms 1-27 isadministered to a patient that had one or more adverse events at apharmaceutical dosage between 60 mg and 160 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 50 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 60 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 70 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 80 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 90 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 100 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 110 mg of Compound 1.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 120 mg of Compound 1.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 130 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 140 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 150 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 160 mg.

In another embodiment, 40 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a pharmaceutical dosage of 140 mg, 100 mg, or 60 mg.

In another embodiment, the pharmaceutical dosage comprising 20 mg freebase equivalent of one or more of Forms 1-27 is administered to apatient that had one or more adverse events at a dosage greater than 60mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a pharmaceutical dosage between 40 mg and 160 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 30 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 40 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 50 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 60 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 70 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 80 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 90 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 100 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 110 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 120 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 130 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 140 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 150 mg.

In another embodiment, 20 mg free base equivalent of one or more ofForms 1-27 is administered to a patient that had one or more adverseevents at a dosage of 160 mg.

In other embodiments, 20 mg free base equivalent of one or more of Forms1-27 is administered to a patient that had one or more adverse events ata pharmaceutical dosage of 140 mg, 100 mg, 60 mg, or 40 mg.

In some embodiments, the adverse event is one or more of diarrhea,stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreasedweight, decreased appetite, nausea, fatigue, oral pain, hair colorchanges, dysgeusia, hypertension, abdominal pain, constipation,increased AST, increased ALT, lymphopenia, increased alkalinephosphatase, hypocalcemia, neutropenia, thrombocytopenia,hypophosphatemia, hyperbilirubinemia, perforations, fistulas,hemorrhage, thromboembolic events, wound complications, osteonecrosis ofthe jaw, proteinuria, reversible posterior leukoencephalopathy syndrome(RPLS), and embryo-fetal toxicity.

In some embodiments, the adverse event is Grade 1. In some embodiments,the adverse event is Grade 2. In some embodiments, the adverse event isGrade 3. In some embodiments, the adverse event is Grade 4. In someembodiments, the adverse event is Grade 5.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 4 adverse event. In another embodiment, upon resolution orimprovement of the Grade 4 adverse event, the dose of Compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 4 adverse event means returning to baseline.In other embodiments, resolution or improvement of the Grade 4 adverseevent means resolution to a Grade 1 adverse event.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 3 adverse event. In another embodiment, upon resolution orimprovement of the Grade 3 adverse event, the dose of Compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 3 adverse event means returning to baseline.In other embodiments, resolution or improvement of the Grade 4 adverseevent means resolution to a Grade 1 adverse event.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 2 adverse event. In another embodiment, upon resolution orimprovement of the Grade 2 adverse event, the dose of Compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 2 adverse event means returning to baseline.In other embodiments, resolution or improvement of the Grade 2 adverseevent means resolution to a Grade 1 adverse event.

In one embodiment, treatment is temporarily suspended for a patient whohad a Grade 1 adverse event. In another embodiment, upon resolution orimprovement of the Grade 1 adverse event, the dose of Compound 1 isresumed at the same or a reduced dosage. In some embodiments, resolutionor improvement of the Grade 1 adverse event means returning to baseline.

In some embodiments, the dose is further reduced one or more timesfollowing the first reduction as a result of one or more adverse events.In one embodiment, the dose is reduced a first time. In anotherembodiment, the dose is reduced a first and second time. In anotherembodiment, the dose is reduced a first, second, and third time.

General Preparation Methods to Prepare Crystalline Solid Forms 1-27

Crystalline solid forms may be prepared by a variety of methodsincluding, but not limited to, for example, crystallization orrecrystallization from a suitable solvent mixture; sublimation; growthfrom a melt; solid state transformation from another phase;crystallization from a supercritical fluid; and jet spraying. Techniquesfor crystallization or recrystallization of crystalline solid forms of asolvent mixture include, but are not limited to, for example,evaporation of the solvent; decreasing the temperature of the solventmixture; crystal seeding of a supersaturated solvent mixture of thecompound and/or salt thereof; crystal seeding a supersaturated solventmixture of the compound and/or a salt from thereof; freeze drying thesolvent mixture; and adding antisolvents (countersolvents) to thesolvent mixture. High throughput crystallization techniques may beemployed to prepare crystalline solid forms including polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals, are discussed in Solid-StateChemistry of Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell,2^(nd) Edition, SSCI, West Lafayette, Ind. (1999).

In a crystallization technique in which solvent is employed, thesolvent(s) are typically chosen based on one or more factors including,but not limited to, for example, solubility of the compound;crystallization technique utilized; and vapor pressure of the solvent.Combinations of solvents may be employed. For example, the compound maybe solubilized in a first solvent to afford a solution to whichantisolvent is then added to decrease the solubility of the Compound 1in the solution and precipitate the formation of crystals. Anantisolvent is a solvent in which a compound has low solubility.

In one method that can be used in preparing crystals, Compound 1 can besuspended and/or stirred in a suitable solvent to afford a slurry, whichmay be heated to promote dissolution. The term “slurry,” as used herein,means a saturated solution of the compound, wherein such solution maycontain an additional amount of compound to afford a heterogeneousmixture of compound and solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promotecrystallization. Seeding may be employed to control growth of aparticular polymorph and/or to control the particle size distribution ofthe solid product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in “ProgrammedCooling Batch Crystallizers,” J. W. Mullin and J. Nyvlt, ChemicalEngineering Science, 1971, 26, 3690377. In general, seeds of small sizeare needed to effectively control the growth of crystals in the batch.Seeds of small size may be generated by sieving, milling, or micronizinglarge crystals, or by microcrystallizing a solution. In the milling ormicronizing of crystals, care should be taken to avoid changingcrystallinity from the desired solid form (i.e., changing to anamorphous or other polymorphic form).

A cooled crystallization mixture may be filtered under vacuum and theisolated solid product washed with a suitable solvent, such as, forexample, cold recrystallization solvent. After being washed, the productmay be dried under a nitrogen purge to afford the desired solid form.The product may be analyzed by a suitable spectroscopic or analyticaltechnique including, but not limited to, for example, differentialscanning calorimetry (DSC); x-ray powder diffraction (XRPD); andthermogravimetric analysis (TGA) to assure the solid form of thecompound has been formed. The resulting solid form may be produced in anamount greater than about 70 weight percent isolated yield, based on theweight of the compound originally employed in the crystallizationprocedure, and preferably greater than about 90 weight percent isolatedyield. Optionally, the product may be delumped by being comilled orpassed through mesh screen.

The features and advantages of this disclosure may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of thisdisclosure that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. The disclosure is further illustrated by the followingexamples, which are not to be construed as limiting the disclosure inscope or spirit to the specific procedures described in them.

Examples

Experimental Techniques:

X-Ray Powder Diffraction (XRPD)

XRPD analyses were performed using a Panalytical Xpert Prodiffractometer equipped with a Cu X-ray tube and a Pixcel detectorsystem. The isothermal samples were analyzed in transmission mode andheld between low density polyethylene films. The Almac default XRPDprogram was used (range 3-40° 2 0, step size 0.013°, counting time 99seconds, about 22 minute run time). XRPD patterns were sorted andmanipulated using HighScore Plus 2.2c software.

Differential Scanning Calorimetry (DSC)

DSC analyses were carried out on a Perkin Elmer Jade DifferentialScanning calorimeter. Accurately weighed samples were placed in crimpedaluminum pans. Each sample was heated under nitrogen at a rate of 10°C./minute to a maximum of 300° C. Indium metal was used as thecalibration standard. Temperatures were reported at the transition onsetto the nearest 0.01 degree. Note that DSC traces within this report maycontain automated peak integrations which calculate DH of fusion. Wheremultiple thermal events are observed at similar temperatures, these DHvalues are prone to significant error.

Thermogravimetric Differential Thermal Analysis (TG/DTA)

Thermogravimetric analyses were carried out on a Mettler ToledoTG/DTA/DSC1 STARe. The calibration standards were indium and tin.Samples were placed in an aluminum sample pan, inserted into the TGfurnace, and accurately weighed. The heat flow signal was stabilized forone minute at 30° C., prior to heating to 300° C. in a stream ofnitrogen at a rate of 10° C./minute.

Dynamic Vapor Sorption (DVS)

Dynamic Vapor Sorption (DVS) was performed using a Hiden AnalyticalInstruments IGAsorp Vapor Sorption Balance. Approximately 30 mg ofsample was placed into a wire mesh vapor sorption balance pan, loadedinto the IGAsorp vapor sorption balance, and held at 25° C.±0.1° C. Thesample was subjected to a step profile from 0 to 90% RH at 10%increments, followed by desorption from 80% RH to 0% RH at 10%increments. The equilibrium criterion was set to 99.0% step completionwithin a minimum of 60 minutes and a maximum of 5 hours for eachincrement. The weight change during the sorption cycle was monitored,allowing for the hygroscopic nature of the sample to be determined. Thedata collection interval was in seconds.

¹H Nuclear Magnetic Resonance spectroscopy (NMR)

NMR analysis was carried out on a Bruker 400 MHz or 500 MHz instrumentin d-DMSO or CDCl₃. Instrumental parameters are listed on the relevantspectrum plots.

Polarized Light Microscopy

Microscopy analyses were carried out on an Olympus BX51 instrument.

Photomicrographs of Compound 1 were obtained at objective lensmagnifications ×10 using a polarized light source.

HPLC

The HPLC method used to determine aqueous equilibrium solubility isoutlined in Table 32. The retention time of Compound 1 was typically19.1±0.2 min and no new peaks were detected during the analysis ofexperimental samples.

TABLE 32 HPLC method for equilibrium solubility analysis of Compound 1.Parameter Conditions HPLC System Waters Alliance 2695 Column PhenomenexGemini C18, 3 μm, 4.6 × 150 mm Oven Temperature 25° C. InjectorTemperature 25° C. Flow Rate 1.2 mL/min Injection Volume 5 mL SampleDiluent DMSO:MeOH:H₂O, 50:40:10, v/v/v Mobile Phase Mobile Phase A:H₂O:CH₃CN 95:5, v/v containing 20 mM NH₄OAc pH 8.0 ± 0.3 Mobile Phase B:CH₃CN 100% Time (minutes) % A % B Gradient 0 95 5 12 55 45 22.5 45 55 300 100 31.5 0 100 34.5 95 5 42 95 5 Run Time 42 minutes DetectorWavelength 240 nm

FT-IR Spectroscopy

FT-IR spectroscopy was carried out on a Thermonicolet Avatar 370 FT-IRspectrometer equipped with a Golden Gate ATR. Spectra were processedusing GRAMS AI v8.0 software.

Materials and Reagents:

The acids and cocrystal formers used in the salt/cocrystal screeninclude mineral, sulfonic, and carboxylic acids. Isethionic acid wassupplied as the sodium salt, and the free acid form was subsequentlyliberated by ion exchange chromatography.

Experimental Examples

The synthesis of Compound 1, and various polymorphic forms thereof, aredisclosed in U.S. patent application Ser. No. 15/118,738, the entirecontents of which is incorporated herein by reference.

Example 1: Preparation of Isethionic Acid from the Corresponding SodiumSalt

Isethionic acid was prepared from its sodium salt by ion exchangechromatography. Isethionic acid sodium salt (105.5 mg) in water (5 mL)was added to the washed resin (2.5 g), and the mixture was stirred atambient temperature for 4 days. The mixture was filtered, and the resinwas washed with water (about 4 mL). The filtrate was added to a 10 mLvolumetric flask and filled to the mark with water affording about 0.07Misethionic acid solution.

Example 2: Screening Methods

Screening experiments were carried out at a scale of about 40 mg with1:1 stoichiometry and 0.5:1 stoichiometry (API: acid). A range ofmethods for salt formation were carried out including precipitations,slurries, sonications, and evaporations.

Example 3: Preparation of Stock Solutions

Compound 1 (1.28 g) was added to a 50 mL volumetric flask, and THF/water(80:20) was added to the mark to form a 0.052M solution. This wassonicated in the water bath to ensure complete dissolution. Separately,Compound 1 (1.5 g) was added to a 150 mL volumetric flask, and acetonewas added to the mark to form a 0.02M solution.

The acid solutions were prepared as described in Table 33. Solutions ofsulfonic acids were added directly due to concern over the sulfonic acidreacting with MeOH (Table 34).

TABLE 33 Preparation of acid solutions Amount Mol. of acid MolarityVolume Acid Wt. (mg) Solvent (M) (mL) ascorbic 176.12 176.70 MeOH 0.10010 lactic (L) 90.08 266.5 MeOH 0.148 20 glycolic (hydroxyacetic 76.0569.0 MeOH 0.091 10 citric (monohydrate) 192.13 382.4 MeOH 0.100 20 malic(L) 134.09 139.8 MeOH 0.104 10 succinic (butanedioic) 118.09 266.3 MeOH0.113 20 ketoglutaric 146.1 284.7 MeOH 0.097 20 maleic 116.08 232.8 MeOH0.100 20 malonic 104.06 98.7 MeOH 0.095 10 AcOH 60.05 61.3 MeOH 0.102 10pyroglutamic (L) 129.11 248.1 MeOH 0.096 20 aceturic acid (N- 117.1245.7 MeOH 0.105 20 acetylglycine) gluconic (D) 196.16 61.3 MeOH 0.03110 glucuronic (D) 194.14 377.7 MeOH 0.097 20 glutaric (pentanedioic)132.12 132.1 MeOH 0.100 10 α-ketoglutaric 146.1 284.7 MeOH 0.097 20(oxoglutaric) oxalic 90.04 89.9 MeOH 0.100 10 pyruvic 88.06 61.3 MeOH0.070 10 (2-oxopropanoic) erythritol 122.12 121.3 MeOH 0.099 10 lysine(L) monohydrate 146.19 298.7 MeOH 0.102 20 nicotinamide 122.12 61.3 MeOH0.050 10 tromethamine (TRIS) 121.14 126.7 MeOH 0.105 10 urea 60.06 63.4MeOH 0.106 10 xylitol 152.15 159.9 MeOH 0.105 10

TABLE 34 Amount of sulfonic acids used in screening experiments AmountAcid Mol. Wt. (mg, 1.05 eq) benzene sulfonic 158.18 12.62 ethanesulfonic 110.13 8.78 methane sulfonic 96.11 7.67 p-toluene sulfonic acidmonohydrate 190.22 15.17 ethane-1,2-disulfonic (edisilic) 190.2 15.17isethionic (2-hydroxy-ethane sulfonic) 126.13 10.06

Example 4: Precipitation Experiments in THF/Water (80:20)

Acid solution (1.05 eq) was added to each HPLC vial and allowed toevaporate to dryness. In the case of sulfonic acids and liquidco-formers, these were added directly to the vial. Compound 1 inTHF/water (1.6 mL, 1 eq) was added to each vial, and the solutions werestirred at ambient for 16 hours. Any solids which precipitated wereisolated by centrifugation, the solvent was decanted, and the solidswere dried with filter paper prior to XRPD analysis. Samples whichremained as solutions were uncapped and evaporated, and the solids wereanalyzed by XRPD.

Solids that generated disordered XRPD patterns were slurried in THF (50°C.), EtOH (60° C.), or a mixture of THF/EtOH (50° C.) (see Table 35).The slurries were initially carried out at high temperature (1 hour),then slowly cooled to ambient temperature and slurried at ambienttemperature for 16 hours.

Example 5: Precipitation Experiments in Acetone/THF (97:3)

Acid/co-former (1.05 eq), THF (100 μL), and Compound 1 (1 eq) in acetone(0.02M, 4 mL) were added to each HPLC vial, and the mixtures werestirred and heated at 50° C. for about 1 hour. These were allowed tocool and stirred at ambient temperature for 16-18 hours. If aprecipitate had formed, the solids were isolated by centrifugation, thesolvent was decanted, and the solids were dried with filter paper priorto analysis by XRPD. Reactions which formed solutions were uncapped andevaporated to about 1.5 mL. The solids were isolated as above (see Table36). Any samples which remained as solutions were uncapped andevaporated, and any solids were analyzed by XRPD.

Example 6: Precipitation Experiments in Acetone/THF (97:3)

Acid/co-former (1.05 eq), THF (100 μL), and Compound 1 (1 eq) in acetone(0.02M, 4 mL) were added to each HPLC vial, and the mixtures werestirred and heated at 50° C. for about 1 hour. These were allowed tocool and stirred at ambient temperature for 16-18 hrs. If a precipitateformed, the solids were isolated by centrifugation, the solvent wasdecanted, and the solids were dried with filter paper prior to analysisby XRPD. Reactions which formed solutions were uncapped and evaporatedto about 1.5 mL. The solids were isolated as above (see Table 36). Anysamples which remained as solutions were uncapped and evaporated, andany solids were analyzed by XRPD.

Example 7: Slurry Experiments Using 0.5 Eq of Acid

Acid (0.5 eq) was charged to a vial, and 100 μL of THF added. A Compound1 suspension in acetone (4 mL, 10 mg/mL) was added, and the suspensionswere stirred. The vials were left open to allow the solvent to evaporateto about half volume to increase product yield. The suspensions werestirred at ambient temperature for 5 days, then they were centrifugedand the solvents were decanted. The solids were dried with strips offilter paper and analyzed by XRPD.

Example 8: Experiments Carried Out Using Liquid Acids

Compound 1 (about 40 mg) was charged to an HPLC vial and acid (1 mol.eq.), acetonitrile (100-200 μL) was added, and the slurries were stirredat ambient temperature for 16 hours. The slurries were sampled, and thesolids were analyzed by XRPD.

Example 9: Sonication of Pastes

Acid solution (1 eq) was added to a vial and evaporated to dryness.Sulfonic acids, liquid co-formers, and 4-hydroxybenzoic acid, these wereadded directly to the vial. Compound 1 (about 40 mg, 1 eq) and 200 titof solvent (acetonitrile or acetonitrile/H2O (87:13)) were added, andthe mixture was sonicated at 30% intensity using a Cole-Parmer 130 Wultrasonic processor (3×30 sec). All solids recovered from theseexperiments were analyzed by XRPD.

Example 10: Humidity Stress Experiments

Compound 1 salts were accurately weighed into individual vials. Thevials were placed unsealed into a vial containing a saturated solutionof sodium chloride at 40° C. (75% relative humidity). The salts werestored for 5-7 days prior to visual inspection for deliquescence. Thevials were re-weighed to assess % weight gain/loss, and the solids wereanalyzed by XRPD.

Example 11: Desolvation Experiments

The experiments were carried out by heating the material to just abovethe desolvation temperature on the TG/DTA and holding the material atthat temperature for 15 minutes until desolvation was complete. Thesamples were analyzed by XRPD.

Example 12: HPLC solubility determination about 5 mg of each salt wasadded to a vial with distilled water (1 mL). These were stirred atambient temperature (about 25° C.) for 24 hours. The solution wasisolated by filtration through a 0.2 μm PTFE filter and was analyzed byHPLC for concentration. The pH of the solutions was checked with pHpaper.

Example 13: Preparation of Compound 1 Pyruvate (Form 14) Seeded:

Compound 1 (1000 mg) and acetone (80 mL) were added to a flask andstirred at 35° C. to form a pale white suspension (almost all theCompound 1 was dissolved). A solution of pyruvic acid (184 mg, 1.05 eq)in THF (10 mL) was added. This was washed with a further 5 mL of THF. Aclear solution formed, which was stirred at ambient temperature. Thiswas seeded with Form 14 material and allowed to stir for 18 hours. Theresulting suspension was evaporated to about 40 mL and allowed to stirfor a further 18 hours to maximize the yield. The solids were collectedby filtration and dried on the sinter for about 30 minutes to yield theproduct as a white solid (671 mg, 57% yield).

Unseeded:

Compound 1 (100 mg), acetone/THF (97:3, 2 mL), and pyruvic acid (23.4μL) were stirred at ambient temperature for about 96 hours. The solidswere collected by centrifuge filtration and analyzed by XRPD.

XRPD analysis indicated that the salt was crystalline (FIG. 53A).Polarised light microscopy confirmed crystallinity with some aggregationor agglomeration.

A DSC thermogram of Compound 1 pyruvate was recorded at 10° C./minute. Athermal event, with peak temperature at 183° C., is most likely to bedue to the melt of the salt (FIG. 53B). The material appeared todecompose immediately after the melt. Thermal analysis (TG/DTA) (FIG.53C) showed a small weight loss of about 1.7% between 30-140° C.,probably due to residual moisture/solvent, which suggests that Compound1 pyruvate is an anhydrous form. A broad endotherm was observed at onset157° C. with an associated weight loss of about 11.4%, which correspondsto about 0.85 moles of pyruvic acid. It is suspected that as thematerial melts, pyruvic acid is lost, and the material decomposes.

The hygroscopicity and the sorption properties of Compound 1 pyruvatewere determined using Dynamic Vapor Sorption (DVS). The sample was driedat 0% RH prior to performing the sorption and desorption cycle. Theisotherm (FIG. 53D) showed the total weight gain observed between 0% RHand 80% RH was 0.10% w/w, which indicates that the sample isnon-hygroscopic according to the European Pharmacopoeia classificationand less hygroscopic than both forms of Compound 1 (S)-malate (about0.4% w/w). No significant hysteresis was observed between the sorptionand desorption curves. XRPD analysis (FIG. 53E) of the post DVS sampleshowed the material remained unchanged.

The FT-IR spectrum obtained for the material is shown in FIG. 53F andwas shown to conform to the material structure with all expectedfunctional groups present. The ¹H NMR spectrum of Compound 1 pyruvateconformed to structure and confirmed the ratio of API peaks and acidpeaks to be 1:1 (FIG. 53G).

The 1:1 Compound 1 pyruvate salt was a highly crystalline,non-hygroscopic, anhydrous material with a melting peak temperature at183° C. and an aqueous solubility of about 0.133 mg/mL (pH about 3).Compared to the malate salt of Compound 1, the Compound 1 pyruvate salthas a lower molecular weight (which may result in higher drug loadingcompared to the malate salt of Compound 1), higher solubility, loweraspect ratio, and only one physical form observed to date. The improvedparticle morphology/aspect ratio may lead to improvements infilterability and flow properties compared to the malate salt ofCompound 1. Pyruvate is well tolerated in vivo as it is a natural humanmetabolite.

Example 14: Preparation of Compound 1 Glutarate (Form 20) Seeded:

Compound 1 (1000 mg), acetonitrile (10 mL), and glutaric acid (275 mg,1.05 eq) were added to a glass vial and heated to 50° C. The mixture wasseeded with Compound 1 glutarate and stirred for 30 minutes at 50° C.The mixture was very viscous, therefore a further 3 mL of acetonitrilewas added, stirred for 3 hours, cooled to ambient temperature, andstirred for a further 16-20 hours. A sample was removed from themixture, and the solids were isolated by centrifuge filtration to checkfor reaction completion. The solids were analyzed by XRPD analysis.

The remainder of the material was isolated by filtration and washed withacetonitrile (1 mL). The solids were air dried in the filter funnel.(Yield=1.145 g, 91%) Unseeded:

Compound 1 (100 mg), acetonitrile (1.5 mL), and glutaric acid (27.62 mg)were charged to a vial and heated to 50° C. for 1 hour. The mixture wascooled to ambient temperature and stirred for 96 hours. The experimentremained as a suspension throughout. The solids were collected bycentrifuge filtration and analyzed by XRPD.

XRPD analysis (FIG. 54A) indicated that the salt was highly crystalline.Optical microscopy confirmed the salts crystallinity showingbirefringent irregularly shaped particles.

The DSC thermogram obtained for Compound 1 glutarate is shown in FIG.54B. The thermogram showed one endotherm at onset about 176° C., whichwas attributed to the melt. Thermal analysis by TG/DTA (FIG. 54C) showeda small amount of weight loss (0.5%) between 30-160° C., which may bedue to residual moisture/solvent, suggesting Compound 1 glutarate is ananhydrous form. An endotherm was observed at an onset temperature of175° C., with an associated weight loss of 0.5%.

The hygroscopicity and the sorption properties of Compound 1 glutaratewere determined using Dynamic Vapor Sorption (DVS). The sample was driedat 0% RH prior to performing the sorption and desorption cycle. Theisotherm (FIG. 54D) showed the total weight gain observed between 0% RHand 80% RH was 0.08% w/w, which indicates that the sample isnon-hygroscopic according to the European Pharmacopoeia classificationand less hygroscopic than both forms of Compound 1 (S)-malate (about0.4% w/w). The low weight gain was reflected in the slightly noisy data.No significant hysteresis was observed between the sorption anddesorption curves. XRPD analysis (FIG. 54E) of the post DVS sampleshowed the material remained unchanged.

The FT-IR spectrum obtained for the material (FIG. 54F) was shown toconform to the material structure with all expected functional groupspresent. ¹H NMR spectroscopy (FIG. 54G) showed the material conformed tostructure (API:acid, 1:1).

The 1:1 Compound 1 glutarate salt was a highly crystalline,non-hygroscopic, anhydrous material with a melting peak temperature at178° C. It had an aqueous solubility of 0.016 mg/mL (pH about 3).Compared to malate salt of Compound 1, the Compound 1 glutarate salt hasa lower hygroscopicity lower aspect ratio, and only one physical formobserved to date. The improved particle morphology/aspect ratio may leadto improvements in filterability and flow properties compared to themalate salt of Compound 1. Glutarate is well tolerated in vivo as it isa natural human metabolite.

Example 15: Preparation of Compound 1 Isethionate Monohydrate (Form 27)

0.07 M Isethionic acid solution in water (8.5 mL, 1.2 mol eq) was addedto a glass vial, and the water was evaporated under a flow of N₂.Compound 1 (250 mg) and 2.5 mL of acetone/THF (97:3) were added. Thesuspension was heated at 50° C. for about 30 minutes. The experiment wasslowly cooled to ambient temperature and stirred for about 96 hours. Asample was removed from the mixture, and the solids were isolated bycentrifuge filtration and analyzed by XRPD analysis. XRPD analysisconfirmed pure Form 27 material. The remainder of the material wasisolated by filtration and washed with acetone/THF (97:3) (about 1 mL),and the solids air dried in the filter funnel for 30 minutes (approx.yield 215 mg, 68%).

XRPD analysis (FIG. 55A) indicated that the salt was crystalline.Optical microscopy confirmed the salts crystallinity showingbirefringent needle shaped particles that readily aggregate.

The DSC thermogram obtained for Compound 1 isethionate is shown in FIG.55B and shows two endothermic events consisting of a first thermal eventwith a peak temperature at about 80° C. and a second thermal event witha peak temperature at about 203° C. The TG/DTA trace (FIG. 55C) alsoshows two endotherms, the first endotherm occurs at onset about 49° C.and has an associated weight loss of 3% which corresponds to 1 molarequivalent of water. The second endothermic event at onset about 199° C.is due to the material melting.

The hygroscopicity and the sorption properties of Compound 1 isethionatemonohydrate were determined using Dynamic Vapor Sorption (DVS). Thesample was dried at 0% RH prior to performing the sorption anddesorption cycle. The isotherm (FIG. 55D) showed a plateau of watercontent between 10-50% RH at about 3.0±0.1% w/w (1 mol. eq.). Above 50%RH, an increase in hygroscopicity was observed. The total weight gainobserved between 20% RH and 80% RH was about 2.4% w/w, which impliesthat the hydrated form is hygroscopic. No significant hysteresis wasobserved between the sorption and desorption curves. XRPD analysis (FIG.55E) of the post DVS sample showed the material remained unchanged.

The FT-IR spectrum obtained for the material is shown in FIG. 55F andwas shown to conform to the material structure with all expectedfunctional groups present. The ¹H NMR spectrum of Compound 1 isethionateconformed to structure and confirmed the ratio of API peaks and acidpeaks to be 1:1 (FIG. 55G).

The 1:1 Compound 1 isethionate monohydrate was a crystalline materialwith a melting peak temperature of the anhydrous form at 203° C. It hadan aqueous solubility of 0.195 mg/mL (pH about 2). Compared to malatesalt of Compound 1, the Compound 1 isethionate monohydrate salt has amuch higher solubility.

Example 16: (Crystal Habit Experiment) Temperature Cycling inAcetone/Water (97:3, v/v)

Compound 1 salt (about 30 mg) was weighed into an HPLC vial, and 1 mL ofacetone/water (97:3, v/v) added. The suspension was stirred at 400 rpmand subjected to 15 cycles of the following: 1) Heat from 23° C. to 53°C. at 0.5° C./minute, and 2) Cool from 53° C. to 23° C. at 0.2°C./minute. The samples were centrifuged, the solvents were decanted, andthe solids were dried with strips of filter paper prior to XRPD analysisand optical microscopy.

Example 17: (Crystal Habit Experiment) Vapor Diffusion

Acetone/THF (50:50) was added in 100 μL aliquots to the Compound 1 saltuntil dissolution was almost reached. The suspension was filteredthrough a 0.2 μm filter into an HPLC vial, and this was placed inside aglass vial containing heptane. In the case of Compound 1 glutarate,seeds of glutarate salt were added to the solution. The solutions wereleft to stand at ambient temperature until sufficient solids wereobserved (3-6 days). The samples were centrifuged, the solvents weredecanted, and the solids were dried with strips of filter paper prior toXRPD analysis and optical microscopy. Compound 1 salt (about 20 mg) wasadded to an HPLC vial, and the solid was dissolved in 200 μL of THF/H2O(80:20). The vial was placed uncapped into a glass vial containingacetone. Solids were collected by decanting solvent and drying thesolids with strips of filter paper. XRPD analysis and optical microscopywere carried out on the solids.

Example 18: (Crystal Habit Experiment) Slow Evaporation from Acetone/THF

Compound 1 salt (about 20 mg) was dissolved in 1 mL of acetone/THF(50:50). The vial was covered with perforated aluminium foil and left toevaporate at ambient temperature. The solids were analyzed by XRPD andoptical microscopy.

Example 19: (Crystal Habit Experiment) Slurry in Chloroform

Compound 1 pyruvate or glutarate (about 20 mg) was slurried in CDCl₃(200-500 μl) at 50° C. for 24 hours. For isethionate, no solids werepresent, and the solution was cooled to ambient temperature and stirredfor 6 days. Solids were collected by centrifugation and decantation ofsolvent, and the solids were dried with strips of filter paper. XRPDanalysis and optical microscopy were carried out on the solids.

Example 20: (Crystal Habit Experiment) Slurry in EtOH

Compound 1 pyruvate or isethionate (about 20 mg) was slurried in EtOH(500 μL) at 50° C. for 24 hours, and the solids were collected bycentrifugation and decantation of solvent. The solids were dried withstrips of filter paper. XRPD analysis and optical microscopy werecarried out on the solids. Compound 1 glutarate (about 20 mg) and EtOH(1 mL) were added to a vial. Dissolution was observed. The vial wascovered with perforated aluminium foil, and the solvent evaporated. XRPDanalysis and optical microscopy were carried out on the solids.

Example 21: Salt/Cocrystal Screening

Part A: Solvent Based Screening Techniques

Solvent based experiments were performed on approximately 40 mg scale inglass vials. The methods employed are described in detail herein.Evaporation, precipitation, sonication, and slurry (at ambient andelevated temperatures) are good methods for salt formation and were usedin this screen.

Part B: Precipitation/Slurry Experiments

Precipitation experiments were carried out by mixing API and acid inTHF/H₂O (80:20) or THF/acetone (97:3) and isolating any precipitatedsolids. Any experiments which remained as solutions were evaporated, andany solids generated were analyzed by XRPD. Solids which exhibited newXRPD patterns were further analyzed by ¹H NMR spectroscopy and TG/DTAanalysis to confirm stoichiometry and solvent content. Table 35 showsthe results from the precipitation/slurry experiments carried out inTHF/H₂O (80:20). Five of the experiments from THF/H₂O (80:20) gaveprecipitates with unique crystalline XRPD patterns (Forms 1-5). Theremaining experiments were evaporated, and any solids isolated wereanalyzed by XRPD. In an attempt to generate more crystalline material,the solids were re-slurried in THF, THF/EtOH, or EtOH as describedherein, yielding Forms 15 and 16.

TABLE 35 Results of precipitation experiments in THF/H₂O (80:20) PptXRPD XRPD Acid/Co-former formed Evap (solids formed) Slurry after slurryascorbic no yes disordered Form I — — benzene sulfonic no yes disorderedTHF at 50° C. Form 15 citric yes no Form 1 — — ethane sulfonic no yesdisordered THF at 50° C. solution glycolic no yes disordered Form I —lactic (L) no yes Form I — malonic yes yes Form 2 — methane sulfonic noyes very disordered THF at 50° C. Form 16 p-toluene sulfonic no yesdisordered THF at 50° C. disordered pyroglutamic (L) no yes disorderedTHF at 50° C. solution succinic no yes disordered solution sulfuric yesno Form 5 — — 4-hydroxybenzoic yes no Form I + — amorphousn-acetylglycine no yes disordered Form II — ethane 1,2- yes no Form 4 —disulfonic gluconic (D) no yes disordered THF at 50° C. Form 26glucuronic (D) no yes disordered EtOH/THF at solution 50° C. glutaric noyes disordered THF at 50° C. Form III isethionic no yes Form I — —2-ketoglutaric no yes disordered EtOH/THF at solution 50° C. oxalic yesno Form 3 — — pyruvic no yes disordered THF at 50° C. solutionerythritol no yes Form I + erythritol — lysine (L) no yes Form I andForm — II nicotinamide no yes Form I — — tromethamine no yes Form I, IIand EtOH at 60° C. solution tromethamine urea no yes Form I — xylitol noyes Form I + extra EtOH at 60° C. Form III peaks

Table 36 shows the results from the precipitation/slurry experimentscarried out in THF/acetone (97:3). Solids were recovered bycentrifugation, decantation of the solvents, and drying with filterpaper prior to analysis by XRPD. Experiments which did not contain solidafter 16 hours were evaporated, and the solids were analyzed by XRPD.Forms 1, 6-14, and 27 were isolated from these experiments.

TABLE 36 results of precipitation experiments in THF/acetone (97:3)Heated to Solids Reaction Acid/co-former 50° C. Dissolved 16 hrs? EvapXRPD type ascorbic yes yes No yes — evap benzene sulfonic yes no Yes —Form 6 slurry citric no yes No yes Form 1 evap ethane sulfonic yes noYes — Form 8 slurry glycolic yes yes No yes Form III evap lactic (L)(1M) yes yes No yes Form III evap malonic yes no Yes — Form 8 slurrymethane sulfonic yes no Yes — Form 9 slurry p-toluene sulfonic yes noYes — Form 10 slurry pyroglutamic (L) yes yes No yes disordered evapForm III succinic yes yes No yes disordered evap Form III sulfuric (1M)yes no Yes — Form 11 slurry 4-hydroxybenzoic no no Yes — Form III slurryn-acetylglycine yes yes slight ppt — Form III + N- pptn. acetylglycineethane 1,2-disulfonic yes no Yes — Form 12 slurry gluconic (D) yesalmost slight ppt — Disordered slurry Form III glucuronic (D) yes almostYes — Form III + slurry Dglucuronic glutaric yes yes No yes Form IIIevap isethionic yes no Yes — Form 27 slurry 2-ketoglutaric no yes No yesdisordered evap oxalic yes no Yes —- Form 13 slurry pyruvic yes yes Noyes Form 14 evap erythritol yes yes slight ppt — Form III + pptn.erythritol lysine (L) yes almost Yes — Form III + slurry disorderednicotinamide yes yes No yes Form III evap tromethamine yes yes slightppt — Form III pptn. urea yes yes No yes Form III evap xylitol yes yesslight ppt — Form III pptn.

Part C: Salt Formations Using 0.5 Molar Equivalents of Co-Former

Salt formations were carried out as detailed herein using 2:1equivalents of API:acid/co-former. Forms 11 and 12 were isolated fromthese experiments. ¹H NMR spectroscopy of Forms 11 and 12 confirmed 2:1ratio of API to acid.

TABLE 37 Screening results from 2:1 (API:acid) stoichiometry experimentsin THF/acetone (97:3) Acid Observations XRPD citric suspensionthroughout Form III + Type 1 sulfuric (0.5M) dissolved and precipitatedForm 11 ethane 1,2-disulfonic suspension throughout Form 122-ketoglutaric suspension throughout Form III + extra peaks oxalicsuspension throughout Form III + Form 13 pyruvic suspension throughoutForm III + extra peaks

Part D: Salt Formation with Liquid Acid and Compound 1

The reactions of Compound 1 in liquid acid in the absence of solvent didnot yield any salts. Therefore, acetonitrile was added, and the mixtureswere slurried for a further 16 hours. Forms 5, 25, and 26 (sulfate,mesylate, and gluconate) were isolated from these reactions.

TABLE 38 Screening results from salt formations with liquid acids AcidSolvent Result XRPD ethane sulfonic none solid Form III lactic (L) (1M)none solid Form III + amorphous methane sulfonic none solid Form III +Type 9 sulfuric (0.5M) none solid amorphous + disordered gluconic (D)none solid Form III pyruvic none solid Form III + amorphous ethanesulfonic acetonitrile solid Type 18 lactic (L) (1M) acetonitrile solidForm I (PS) methane sulfonic acetonitrile solid Form 25 sulfuric (0.5M)acetonitrile solid Form 5 gluconic (D) acetonitrile solid Form 26pyruvic acetonitrile solid Form 14(PS) + extra peaks

Part E: Sonication

Table 39 shows the results of salt formation by sonication. Forms 6, 9,10, 12, 14, 17, 18, 19, 20, 21, 22, and 26 were all isolated from theseexperiments.

TABLE 39 Screening results from sonication experiments Acid Solvent XRPDascorbic CH₃CN Form III + ascorbic acid CH₃CN/H₂O (87:13) Form III +amorphous benzene sulfonic CH₃CN Form 6 CH₃CN/H₂O (87:13) Form 6 + extrapeaks citric CH₃CN Disordered Form III + Form 1 (small amt) CH₃CN/H₂O(87:13) Form 1 disordered ethane sulfonic CH₃CN Form 18 CH₃CN/H₂O(87:13) highly disordered glycolic CH₃CN Form III CH₃CN/H₂O (87:13) FormIII lactic (L) (1M) CH₃CN Form III CH₃CN/H₂O (87:13) Form III malonicCH₃CN Form III (PS) + new peaks CH₃CN/H₂O (87:13) Form III (weak)methane sulfonic CH₃CN Form 9 CH₃CN/H₂O (87:13) weak p-toluene sulfonicCH₃CN Form 10 CH₃CN/H₂O (87:13) Form 22 pyroglutamic (L) CH₃CN Form IIICH₃CN/H₂O (87:13) Form III (weak) succinic CH₃CN Form 17 CH₃CN/H₂O(87:13) Form III sulfuric (0.5M) CH₃CN Form 21 CH₃CN/H₂O (87:13)disordered 4-hydroxybenzoic CH₃CN Form III + extra peaks CH₃CN/H₂O(87:13) Form III + extra peaks n-acetylglycine CH₃CN Form III +N-acetylglycine CH₃CN/H₂O (87:13) Form III ethane CH₃CN Form 121,2-disulfonic CH₃CN/H₂O (87:13) Form 12 gluconic (D) CH₃CN Form 26CH₃CN/H₂O (87:13) amorphous glucuronic (D) CH₃CN Form III + gluconicCH₃CN/H₂O (87:13) disordered glutaric CH₃CN Form 20 + Form III CH₃CN/H₂O(87:13) Form 20 + Form III isethionic CH₃CN Form 19 CH₃CN/H₂O (87:13)disordered 2-ketoglutaric CH₃CN Form III CH₃CN/H₂O (87:13) Form IIIoxalic CH₃CN Form III CH₃CN/H₂O (87:13) Form III pyruvic CH₃CN Form 14CH₃CN/H₂O (87:13) disordered erythritol CH₃CN Form III + erythritolCH₃CN/H₂O (87:13) Form III lysine (L) CH₃CN Form III CH₃CN/H₂O (87:13)Form III nicotinamide CH₃CN Form III + nicotinamide CH₃CN/H₂O (87:13)Form III + nicotinamide tromethamine CH₃CN Form III + tromethamineCH₃CN/H₂O (87:13) Form III urea CH₃CN Form III CH₃CN/H₂O (87:13) FormIII xylitol CH₃CN Form III CH₃CN/H₂O (87:13) Form III

Example 22: Humidity Stress Experiments

Compound 1 salts were stressed at 40° C./75% relative humidity for about7 days and analyzed by XRPD to determine the physical stability atincreased relative humidity. The weight change was also recorded (seeTable 40). Forms 1, 2, 6, 9-14, 16, 19, 21, 22, 24, and 27 showed smallweight changes and no change of form by XRPD analysis, indicating thatthese salts are relatively stable to high relative humidity. Forms 5, 7,15, 17, 18, 25, and 26 showed larger weight changes and/or a change inphysical form after humidity stressing. Compound 1 oxalate (Form 3) hada weight loss of 43.17% but no form change by XRPD analysis, suggestingthat the salt contained a large amount of surface solvent and/or water.

TABLE 40 results from humidity stressing experiments Form Acid % WeightChange XRPD 1 citric −0.94 Form 1 2 malonic +1.02 Form 2 3 oxalic −43.17Form 3 5 sulfuric (0.5M) −51.79 disordered 6 benzene sulfonic −1.37 Form6 7 ethane sulfonic −0.90 Form 4 9 methane sulfonic −0.82 Form 9 10p-toluene sulfonic −0.09 Form 10 11 sulfuric (0.5M) −1.54 Form 11 12ethane 1,2-disulfonic +0.74 Form 12 13 oxalic −0.41 Form 13 + PS 14pyruvic −0.98 Form 14 15 benzene sulfonic −22.01 highly disordered 16methane sulfonic +0.85 Form 16 17 succinic −46.46 Form 23 18 ethanesulfonic +10.35 highly disordered 19 isethionic +2.02 Form 19 20glutaric +0.06 Form 20 + Form III 21 sulfuric (0.5M) +0.02 Form 21 22p-toluene sulfonic −0.25 Form 22 24 malonic +0.22 Form 24 25 methanesulfonic +6.71 highly disordered 26 gluconic (D) +2.52 highly disordered27 isethionic −1.70 Form 27

Example 23: Crystal Habit Investigation of Selected Compound 1 Salts

Investigation into crystal habit was carried out on each of the selectedsalts using a variety of experiments including temperature cycling,vapor diffusion, slow evaporation, and slurry experiments.

Part A: Crystal Habit Experiments on Compound 1 Pyruvate (Form 14)

Compound 1 pyruvate (Form 14) generated from a precipitation of Compound1 and pyruvic acid in THF/acetone, consisted of small irregularly shapedparticles. Attempts to increase the particle size were made bytemperature cycling, vapor diffusion, slurries and slow evaporation. Thesolids were analyzed by XRPD analysis upon recovery. Slurrying inethanol afforded Compound 1 (Form III), and vapor diffusion inacetone/THF with heptane yielded solids with a weak/amorphous XRPDdiffractogram. Temperature cycling in acetone/water increased theparticle size. Vapor diffusion using THF/water (80:20) as the solventand acetone as the anti-solvent yielded very large crystals. Slurryingin chloroform and slow evaporation from acetone/THF caused nosignificant change in crystal habit.

Part B: Crystal Habit Experiments on Compound 1 Glutarate (Form 20)

Compound 1 glutarate (Form 20) formed from a slurry of Compound 1 andglutaric acid in acetonitrile consisted of small irregularly shapedparticles. Attempts to increase the particle size were made bytemperature cycling, vapor diffusion, slurries and slow evaporation. Thesolids remained as Form 20 except the solids isolated from slurrying inethanol, which yielded Form III material. Temperature cycling inacetone/water (97:3% v/v) greatly increased particle size and largeblock-like particles (30-50 μm) were observed. Vapor diffusion usingacetone/THF (50:50) as the solvent and heptane as the anti-solventafforded larger elliptical shaped particles, which may improvefilterability. Slurrying in chloroform, slow evaporation fromacetone/THF, and vapor diffusion using THF/H₂O (80:20) as the solventand acetone as the anti-solvent showed no significant change in crystalhabit.

Part C: Crystal Habit Experiments on Compound 1 Isethionate Monohydrate(Form 27)

Compound 1 isethionate (Form 27) isolated from a slurry of Compound 1and isethionic acid in acetone/THF consisted of needle like particles.Attempts to increase the particle size were made by temperature cycling,vapor diffusion, slurries and slow evaporation. The solids were analyzedby XRPD analysis upon recovery. Form 27 material was only recovered fromtwo experiments: temperature cycling in acetone/water and vapordiffusion in THF/water with acetone. Temperature cycling slightlyincreased needle size and also gave some large block-like particles.Vapor diffusion from THF/water (80:20) solvent using acetone as theanti-solvent yielded longer acicular particles which may causedifficulties in filtration. A new pattern was observed from slurrying inEtOH, and ¹H NMR suggests it is an ethanol solvate of the salt. Vapordiffusion using acetone/THF (50:50) as the solvent and heptane as theanti-solvent generated solids with a new XRPD pattern. ¹H NMRspectroscopy showed the material to be free base related. Slowevaporation from acetone/THF (50:50) afforded Form III solids.

OTHER EMBODIMENTS

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled.

1. Crystalline solid salts ofN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), wherein the salts areselected from the group consisting of:N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•pyruvate;N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•glutarate; andN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•isethionate monohydrate. 2.Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•pyruvate of claim 1,characterized as Form 14, wherein the crystalline solid comprisesCompound 1 and pyruvate in a 1:1 molar ratio.
 3. Crystalline solidCompound 1•pyruvate, characterized as Form 14, according to claim 2,wherein the Form 14 is characterized by one or more peaks in an XRPDpattern selected from the group consisting of 7.84, 8.81, 11.58, 15.67,16.30, 16.55, 17.67, 17.92, 18.00, 18.20, 18.62, 19.66, 20.54, 20.75,23.84, 26.35, and 26.42 degrees on a 2-theta scale.
 4. Crystalline solidCompound 1•pyruvate, characterized as Form 14, according to claim 2 orclaim 3, wherein the Form 14 is characterized by the peaks at 8.81,11.58, 17.67, 18.00, 23.84, and 26.35 degrees on a 2-theta scale in anX-ray powder diffraction spectrum.
 5. Crystalline solid Compound1•pyruvate, characterized as Form 14, according to any one of claims2-4, wherein the Form 14 is characterized by an XRPD pattern accordingto FIG.
 5. 6. Crystalline solid Compound 1•pyruvate, characterized asForm 14, according to claim 2, wherein the Form 14 is characterized by athermal event with peak temperature at about 183° C. in a differentialscanning calorimetry (DSC) thermogram recorded at 10° C./min. 7.Crystalline solid Compound 1•pyruvate, characterized as Form 14,according to claim 2, wherein the Form 14 is characterized by a broadendotherm at an onset temperature of about 157° C., with an associatedweight loss of about 11.4% as measured by thermogravimetric differentialThermal analysis (TG/DTA).
 8. Crystalline solid Compound 1•pyruvate,characterized as Form 14, according to claim 2, wherein the Form 14 ischaracterized by a total weight gain between 0% relative humidity and80% relative humidity of about 0.10% w/w, as measured by dynamic vaporsorption (DVS).
 9. Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•glutarate of claim 1,characterized as Form 20, wherein the crystalline solid comprisesCompound I and glutarate in a 1:1 molar ratio.
 10. Crystalline solidCompound 1•glutarate, characterized as Form 20, according to claim 9,wherein the Form 20 is characterized by one or more peaks in an X-raypowder diffraction spectrum selected from the group consisting of 8.06,11.77, 19.97, 20.21, 22.27, 23.11, 23.17, 25.81, 25.87, 26.00, and 26.06degrees on a 2-theta scale.
 11. Crystalline solid Compound 1•glutarate,characterized as Form 20, according to claim 9 or claim 10, wherein theForm 20 is characterized by the peaks at 8.06, 11.77, 20.21, 22.27,23.11, 25.81, 25.87, and 26.00 degrees on a 2-theta scale in an X-raypowder diffraction spectrum.
 12. Crystalline solid Compound 1•glutarate,characterized as Form 20, according to any one of claims 9-11, whereinthe Form 20 is characterized by an XRPD pattern according to FIG.
 7. 13.Crystalline solid Compound 1•glutarate, characterized as Form 20,according to claim 9, wherein the Form 20 is characterized by a thermalevent with peak temperature at about 176° C. in a differential scanningcalorimetry (DSC) thermogram recorded at 10° C./min
 14. Crystallinesolid Compound 1•glutarate, characterized as Form 20, according to claim9, wherein the Form 20 is characterized by an endotherm at an onsettemperature of about 175° C., with an associated weight loss of about0.5% as measured by thermogravimetric differential Thermal analysis(TG/DTA).
 15. Crystalline solid Compound 1•glutarate, characterized asForm 20, according to claim 9, wherein the Form 20 is characterized by atotal weight gain between 0% relative humidity and 80% relative humidityof about 0.08% w/w, as measured by dynamic vapor sorption (DVS). 16.Crystalline solidN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1)•isethionate monohydrate ofclaim 1, characterized as Form 27, wherein the crystalline solidcomprises Compound 1 and isethionate in a 1:1 molar ratio. 17.Crystalline solid Compound 1•isethionate monohydrate, characterized asForm 27, according to claim 16, wherein the Form 27 is characterized byone or more peaks in an X-ray powder diffraction spectrum selected fromthe group consisting of 6.56, 12.39, 12.59, 13.14, 16.57, 17.55, 21.68,23.66, 24.33, 26.09, 26.53, 26.69, and 27.40 degrees on a 2-theta scale.18. Crystalline solid Compound 1•isethionate monohydrate, characterizedas Form 27, according to claim 16 or claim 17, wherein the Form 27 ischaracterized by the peaks at 12.39, 12.59, 17.55, 21.68, 23.66, 24.33,and 26.09 degrees on a 2-theta scale in an X-ray powder diffractionspectrum.
 19. Crystalline solid Compound 1•isethionate monohydrate,characterized as Form 27, according to any one of claims 16-18, whereinthe Form 27 is characterized by an XRPD pattern according to FIG.
 9. 20.Crystalline solid Compound 1•isethionate monohydrate, characterized asForm 27, according to claim 16, wherein the Form 27 is characterized bya first thermal event with a peak temperature at about 80° C. and asecond thermal event with a peak temperature at about 203° C. in adifferential scanning calorimetry (DSC) thermogram recorded at 10°C./min.
 21. Crystalline solid Compound 1•isethionate monohydrate,characterized as Form 27, according to claim 16, wherein the Form 27 ischaracterized by a first endotherm at an onset temperature of about 49°C., with an associated weight loss of about 3%, and a second endothermat an onset temperature of about 196° C., with no associated weight lossas measured by thermogravimetric differential Thermal analysis (TG/DTA).22. Crystalline solid Compound 1•isethionate monohydrate, characterizedas Form 27, according to claim 16, wherein the Form 27 is characterizedby a total weight gain between 20% relative humidity and 80% relativehumidity of about 2.4% w/w, as measured by dynamic vapor sorption (DVS).23. A pharmaceutical composition comprising a therapeutically effectiveamount of a substantially pure crystalline solid form of a salt ofCompound 1 as recited by any one of claims 1-22 and a pharmaceuticallyacceptable carrier.
 24. A pharmaceutical composition comprising atherapeutically effective amount of a mixture of crystalline solid formsof a salt of Compound 1 as recited by any one of claims 1-22 and apharmaceutically acceptable carrier.
 25. A method of treating cancercomprising administering to a subject a therapeutically effective amountof a crystalline solid form of a salt of Compound 1 as recited by anyone of claims 1-22.
 26. A method of treating cancer comprisingadministering to a subject a pharmaceutical composition as recited byany one of claims 23-24.
 27. The method of any one of claims 25-26,wherein the cancer is selected from thyroid cancer, stomach cancer,esophageal carcinoma, kidney cancer, liver cancer, ovarian carcinoma,cervical carcinoma, bladder cancer, large bowel cancer, small bowelcancer, brain cancer, lung cancer, bone cancer, prostate carcinoma,pancreatic carcinoma, skin cancer, bone cancer, lymphoma, solid tumors,Hodgkin's disease, or non-Hodgkin's lymphoma.
 28. The method of claim27, wherein the thyroid cancer is medullary thyroid cancer.
 29. Themethod of claim 27, wherein the kidney cancer is renal cell carcinoma.30. The method of claim 27, wherein the liver cancer is hepatocellularcarcinoma.
 31. The method of claim 27, wherein the brain cancer is anastrocytic tumor.
 32. The method of claim 31, wherein the astrocytictumor is selected from a glioblastoma, a giant cell glioblastoma, and agliosarcoma.
 33. The method of claim 32, wherein the glioblastomapossesses oligodendroglial components.
 34. The method of claim 27,wherein the lung cancer is non-small cell lung cancer.
 35. The method ofclaim 27, wherein the prostate carcinoma is castration resistantprostate cancer.
 36. A method of treating diseases or disordersassociated with uncontrolled, abnormal, and/or unwanted cellularactivities due to cMET or RET overexpression, comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of at least one solid form of Compound 1 as recited by any one ofclaims 1-22.
 37. A method of treating diseases or disorders associatedwith uncontrolled, abnormal, and/or unwanted cellular activities due tocMET or RET overexpression, comprising administering to a subject inneed of such treatment a therapeutically effective amount of apharmaceutical composition as recited by any one of claims 1-22.